key: cord-0746974-q5cmnqz1 authors: Stanke-Labesque, Françoise; Gautier-Veyret, Elodie; Chhun, Stephanie; Guilhaumou, Romain title: Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment date: 2020-07-11 journal: Pharmacol Ther DOI: 10.1016/j.pharmthera.2020.107627 sha: 38db3f15f748a1088978d4070647567633d41a17 doc_id: 746974 cord_uid: q5cmnqz1 Inflammation is an evolutionary process that allows survival against acute infection or injury. Inflammation is also a pathophysiological condition shared by numerous chronic diseases. In addition, inflammation modulates important drug-metabolizing enzymes and transporters (DMETs), thus contributing to intra- and interindividual variability of drug exposure. A better knowledge of the impact of inflammation on drug metabolism and its related clinical consequences would help to personalize drug treatment. Here, we summarize the kinetics of inflammatory mediators and the underlying transcriptional and post-transcriptional mechanisms by which they contribute to the inhibition of important DMETs. We also present an updated overview of the effect of inflammation on the pharmacokinetic parameters of most of the drugs that are DMET substrates, for which therapeutic drug monitoring is recommended. Furthermore, we provide opinions on how to integrate the inflammatory status into pharmacogenetics, therapeutic drug monitoring, and population pharmacokinetic strategies to improve the personalization of drug treatment for each patient. The paradigm of personalized medicine aims to provide the right treatment at the right dose for each patient. A global knowledge of the patient, including his/her way of life, comorbidities, medications, and pharmacogenotypes, is required to propose such personalized pharmacological treatment. Certain lifestyle, social, and environmental factors have been suggested to promote systemic chronic inflammation, which can, in turn, lead to disease, such as cardiovascular disease (Ketelhuth et al., 2019) , chronic infectious disease and cancer (Deeks et al., 2013) , diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, and autoimmune and neurodegenerative disorders (Furman et al., 2019) . In addition, people face acute infections or injury episodes throughout their life that are resolved by intermittent increases in inflammation. Yet, several papers have suggested that inflammation can modulate drug-metabolizing enzyme and transporter (DMET) activity (Morgan, 2017; Shah & Smith, 2015) . Therefore, a better knowledge of the impact of inflammation on DMETs and its related clinical consequences would help to understand inter and intraindividual variability of drug exposure and better manage drug exposure J o u r n a l P r e -p r o o f Journal Pre-proof for each patient. Indeed, the clinical response to most drugs, i.e. efficacy or toxicity, is related to exposure to the drug or its active metabolites. Several complementary pharmacological approaches have helped to ensure the most adapted drug exposure for each patient (Tucker, 2017) , but few have addressed inflammation as a major source of drug pharmacokinetic variability. Pharmacogenetics allows the identification of genetic variants, the presence of which can strictly contraindicate the use of a drug (HLA-B*5701 for abacavir) or contribute to explain interindividual pharmacokinetic or pharmacodynamic variability (Lauschke et al., 2019) . Consequently, the determination of genotypes helps to predict a patient's phenotype and therefore to propose the right first dose of a drug when a treatment is initiated (Thervet et al., 2010) . However, a study performed on 114 Hungarian liver donors reported that the CYP2C19 phenotype was wellpredicted by genotypic data in only 40% of patients (Kiss et al., 2018) . These data suggest that the prediction of metabolic capacity based on the determination of pharmacogenetic polymorphisms may be blunted by other determinants, including co-medication that interferes with DMETs or any inflammatory comorbidities that may have occurred during the lifetime of an individual (Shah & Smith, 2015) . Therapeutic drug monitoring makes it possible to verify the total exposure to narrow therapeutic index drugs. It is a useful approach to ensure the longitudinal pharmacological follow-up of patients with chronic treatment (i.e., immunosuppressants, antipsychotics, antifungals) and adapt the dose for each patient whenever intrinsic or external changes occur. Liver or kidney function or comedication with drugs that affect DMETs are well-known variables that can affect drug exposure. However, the influence of inflammation has received less attention. Finally, pharmacokinetic models are useful tools to predict inter-dose plasma exposure to escalate or de-escalate the dose of a drug (Petitcollin et al., 2019) during pharmacological follow-up. In addition to demographic information, these models consider classical features that contribute to inter-or intraindividual variability of drug exposure. However, the inflammatory status of the patient increase in the level of serum inflammatory cytokines and NO (De-Oliveira et al., 2015) , suggesting that pro-inflammatory cytokines and NO may be intermediate molecular links between inflammation and CYP downregulation (Shah & Smith, 2015) . Moreover, deletion of the gene encoding IL-6 prevented the down-regulation of CYP2D and CYP3A in Clostridium rodentiuminfected mice, whereas the down-regulation of CYP4A remained unchanged (Nyagode et al., 2010) . Furthermore, deletion of the gene encoding IFN-γ prevented the LPS-induced downregulation of CYP2D, whereas it did not affect the inhibition of CYP3A and CYP4A in the same experimental model (Nyagode et al., 2010) . These findings show heterogeneous effects of cytokines on CYP expression and activity, with differences in magnitude, potency (Dickmann et al., 2011) , and time-course, depending on the administered infectious agent (see Table 2 ). Similar downregulation of DMETs in preclinical models of certain chronic inflammatory diseases has been recently reviewed (Wu & Lin, 2019) . Various models of colitis (Chaluvadi, Kinloch, et al., 2009; Masubuchi et al., 2008) and arthritis (Ashino et al., 2007; Dickmann et al., 2012; Sanada et al., 2011) show diminished hepatic expression and/or activity of many CYP450 enzymes (CYP3A, 4A, 2C, 1A2, and 2E1). Such down-regulation appears to correlate with an increase in proinflammatory cytokine concentrations (IL-6 and TNF-α, as well as IFN-γ, IL-2, IL-1α, and IL-1β) (Chaluvadi, Kinloch, et al., 2009; Masubuchi et al., 2008; Sanada et al., 2011) and could explain the increased concentrations of propranolol (Guirguis & Jamali, 2003) and verapamil (Ling & Jamali, 2005) observed in adjuvant-induced arthritis. IL-6 is one of the most abundant cytokines released in the plasma of infected mice (Chaluvadi, Kinloch, et al., 2009) . IL-6 represses CYP3A4 expression (Yang et al., 2010) and decreases CYP3A-dependent clearance in a dose-dependent manner in human hepatocyte cells in culture (Dickmann et al., 2011) . Moreover, pretreatment of human hepatocytes with an IL-6 monoclonal antibody inhibited the decrease in IL-6-induced CYP3A clearance (Dickmann et al., 2011), providing definitive proof for the contribution of IL-6 in reducing CYP3A-dependent clearance. However, the inhibitory effect of IL-6 is not limited to CYP3A, as a large panel of CYPs was also J o u r n a l P r e -p r o o f shown to be down-regulated in murine models of infection (Table 2) , a genetic murine model of arthritis (Ashino et al., 2007) , and cultured hepatocytes (Aitken & Morgan, 2007) . Similar experiments have also suggested a major role of TNF-⍺ in CYP downregulation, as deletion of the gene encoding the TNF-⍺ receptor (Kinloch et al., 2011) or treatment with a biologic drug that neutralizes soluble TNF-⍺ prevented the downregulation of CYP3A11 and CYP3A25 in Citrobacter rodentium-infected mice. Infliximab treatment of preadjuvant arthritic rats resulted in significantly higher total CYP protein content than that in untreated pre-adjuvant arthritic rats (Ling & Jamali, 2009) . These data, along with those from in vitro hepatocyte experiments showing that TNF-⍺ powerfully regulates CYP levels (Kinloch et al., 2011; Nyagode et al., 2010) , provide strong evidence for the role of TNF-⍺ in CYP downregulation. Conversely, several studies reported induction of certain CYPs: CYP2D9 in rodents models of infectious colitis (Chaluvadi, Kinloch, et al., 2009; Chaluvadi, Nyagode, et al., 2009) or diabetes (Gwak et al., 2020 ) (see Table 2 ), CYP3A13 in mice with collagen antibody-induced arthritis (Dickmann et al., 2012) or oral infection by Citrobacter rodentium (Richardson et al., 2006a) , CYP4A and CYP2E subfamilies in LPS-treated F344 rats (Morgan, 1997) . Experimental studies performed in various rodent models of diabetes (Wu & Lin, 2019) have also provided conflicting results in terms of expression of DMETs, with expression and activity either increased (Yoshinari et al., 2006) or decreased (Ghose et al., 2011) . All these discordant results could be related to the differences in rodent species (rat vs mice) and strains (Sprague-Dawley rats vs Zucker diabetic fatty rat for example), and inflammatory stimuli that were used (injection of LPS, chemical irritant or infectious agent) in different experimental conditions (see Table 2 and the review of Morgan et al (Morgan, 1997) ). The effect of inflammation on other enzymes involved in drug metabolism and on transporters has received less attention. Infection by Citrobacter rodentium (Kinloch et al., 2011) or Plasmodium chabaudi (Mimche et al., 2019) significantly reduces hepatic flavin monooxygenase mRNA levels. Infection by Plasmodium chabaudi (Mimche et al., 2019) or Clostridium rodentium or treatment J o u r n a l P r e -p r o o f with LPS (Richardson et al., 2006b) significantly downregulated several genes encoding the hepatic UDP-GT1A1, 1A9, and several of those of the UGT2B subfamily, an effect associated with the reduced expression of UDP-GT1A1 and UDP-GT2B protein. Again, the effect of inflammation on UDP-GT regulation appears to be cytokine-dependent and UDP-GT isoform specific, as also reported for CYP. However, IL-6 downregulates most phase 2 enzymes involved in drug metabolism in human primary hepatocytes (Keller et al., 2016 ). An in vitro study on human liver microsomes suggested that certain nonsteroidal anti-inflammatory drugs may have an inhibitory potential on UDP-GT isoforms, suggesting that certain mediators of the cyclooxygenase-dependent pathway may be involved in the regulation of DMET activity. However, the underlying mechanism and the clinical relevance in terms of UDP-GT substrate clearance need to be further investigated (Joo et al., 2015) . The hepatic transporters involved in drug clearance belong to two gene families, ATP-binding cassette (ABC) and SLC. Significant down-regulation of hepatic mRNA levels of SLC22a4, SLCOa4, and SLCO2b1, as well of ABCb1, ABCg2, has been reported in Citrobacter rodentiuminfected mice relative to controls . This effect was blocked in infected mice lacking IL-6 or TNF⍺ , again suggesting a key role of these cytokines in the downregulation of certain SCL and ABC transporters. A study on primary human hepatocytes challenged with IL-6 has extended these findings to numerous transporters of the ABC and SLC families (Keller et al., 2016) . The binding of pro-inflammatory cytokines to their specific receptors leads to the activation of several transcription factors, including NF-κB. The direct binding of NF-κB to DMET promoter regions inhibits the heterodimerization of nuclear retinoid x receptor (RXR)-α to constitutive androstane/active receptor (CAR), pregnane X receptor (PXR), and peroxisome proliferator activation receptor (PPAR) nuclear receptors. Yet, the heterodimerization of RXR to other nuclear receptors plays a central role in the regulation of genes encoding DMETs (Keller et al., 2016; Wu & Lin, 2019) . Moreover, inflammation related to Plasmodium chabaudi is associated with the downregulation of CAR and farnesoid X receptor (FXR) and, to a lesser extent, PXR and RXR J o u r n a l P r e -p r o o f mRNA (Mimche et al., 2019) . Thus, within the complex network that links transcriptional factors with the expression of DMET, NF-κB pathway activation by pro-inflammatory cytokines contributes to the inhibition of DMET transcription observed during inflammation (Keller et al., 2016) . Several studies have suggested that post-transcriptional mechanisms may also modulate CYP activity. A chronic allergic murine model induced by repeated administration of ovalbumin showed down-regulation of CYP 1A2, CYP2C, 2E1, and CYP3A activity, although CYP protein expression remained unchanged relative to that of control animals (Tanino et al., 2019) . IL-1β challenge in cultured rat hepatocytes decreased CYP3A1 protein expression by 40% and reduced its activity within 6 h (Lee et al., 2009) . Such rapid kinetics suggest that post-transcriptional mechanisms may be involved in the early downregulation of CYP3A1. Several studies have reported that early cytokine-mediated downregulation of CYP is inhibited by a NO synthase inhibitor (Carlson & Billings, 1996) or proteasome inhibitor (Lee et al., 2009; Morgan, 2017) . Similarly, effective inhibition of NO synthase reduced the hydrolase activity of several CYP enzymes but did not impair the downregulation of CYP2C29 or CYP3A11 mRNA expression or CYP2C, CYP2E, or CYP34 protein expression in rats treated with LPS (Sewer et al., 1998) . Finally, native CYP2B6 protein was rapidly downregulated in HeLa cells within 3 h of treatment with a NO donor, whereas the level of its mRNA was not . These data all suggest that NO and proteasomedependent pathways are likely to be involved in the early phase of CYP protein downregulation. Activation of the inducible NO synthase (Mimche et al., 2019) promoted by IL-1β, IFN-γ, and TNF-⍺ during the inflammatory response leads to increased NO synthesis and release, which in turn reduces CYP activity through reversible binding to the heme moiety or tyrosine and cysteine Snitrosilation or nitration. In addition, NO induces proteasome-dependent CYP3A4 inhibition, as a proteasome inhibitor blocks IL-1 and NO-induced downregulation of CYP3A4 (Lee et al., 2009) . Given that IL-1β is a cytokine synthesized during the initial phase of the inflammatory response, these data all suggest that the functional inhibition of CYP activity occurs early in the inflammatory process. J o u r n a l P r e -p r o o f Epigenetic changes regulate the expression and activity of genes involved in DMETs, as recently reviewed (Lauschke et al., 2019) , and contribute to interindividual differences in drug responses (Ivanov et al., 2014) . The level of DNA methylation in the promoters of several CYPs (CYP3A4, CYP1A2, CYP2C19 and UDP-GT1A4) inversely correlates with their levels of expression in adult liver (Habano et al., 2015) . Similarly, the modification of histone patterns inversely correlates with the level of expression of several drug transporters (ABCb1, ABCg2) in prostate carcinoma (Henrique et al., 2013) . Consequences on DMET expression or activity are expected, as inflammation itself also induces epigenetic regulation of the innate immune response (Zhang & Cao, 2019) and triggers the release of certain miRNAs from immune cells (Kugler et al., 2020) . Indeed, methylation levels at the CYP11A1 locus significantly correlate with CRP levels in the serum of patients with bipolar mania, suggesting an association between inflammation and epigenetic changes of CYP (Sabunciyan et al., 2015) . Furthermore, miRNAs have been reported to contribute to the variability of CYP, including reduced expression and activity of CYP2C9, CYP2C8, CYP2C19 (Rieger et al., 2015) , CYP2D6 (Zeng et al., 2017) and CYP3A4 (Kugler et al., 2020) . A recent study evidenced upregulation of several miRNAs in livers from donors with elevated CRP concentrations compared to those with a normal concentration (Kugler et al., 2020) . Some of these miRNAs were able to attenuate DMET expression and activities or to target nuclear receptors to block gene transcription, CYP2C19 and CYP3A4 being the top downregulated. In summary (see Figure 1 ), these data all suggest that acute or chronic inflammation can inhibit the level and activity of major CYPs and, to a lesser extent, type 2 enzymes and ABC and SLC transporters involved in drug pharmacokinetics. These inhibitory effects may occur both in the intestine (Simon et al., 2019) and liver, leading to impaired absorption and pre-systemic and hepatic metabolic phenoconversion. In acute inflammation, phenoconversion would result in a shift towards poorer metabolizing phenotype, providing there are no other cause of inhibition. In chronic inflammation, treatment with a drug that inhibits the inflammatory pathway (i.e. IL-6 monoclonal antibody) might revert the phenotype to its physiological status, providing there is no other cause J o u r n a l P r e -p r o o f of induction. Thus, inflammation can contribute to the intra and interindividual variability of drug responses. Approximately 80% of all drugs are primarily metabolized by CYP isoforms, notably CYP1A2, 2D6, 3A4, 2C9, and 2C19. As a consequence, inflammation could theoretically influence their pharmacokinetics. This point is of high clinical relevance for drugs with a narrow therapeutic index, which are candidates for TDM. Table 3 presents the effect of inflammation on the blood or plasma exposure and/or pharmacokinetic parameters of the main drugs for which TDM is routinely performed. Table 3 ) Numerous studies have highlighted the impact of inflammation on clozapine metabolism. Several case reports have described elevated concentrations of clozapine in patients experiencing acute inflammatory episodes associated with clinical signs of intoxication (de Leon & Diaz, 2003; Haack et al., 2003; Jecel et al., 2005) . However, an increase in the clozapine and norclozapine trough concentration (Cmin) and clozapine concentration/dose ratio (C/D) was observed in two patients, without symptoms of intoxication (Ruan et al., 2018) . This link between the inflammatory status and clozapine pharmacokinetics was later confirmed by retrospective comparative studies using CRP levels as a marker of inflammation. Several studies on retrospective TDM data have reported an impact of abnormal CRP values on the clozapine concentration and C/D and a decrease in the metabolic clozapine/norclozapine ratio (Hefner et al., 2016; Pfuhlmann et al., 2009) . Unfortunately, safety data were not available in these studies. Little data are available for other antipsychotic drugs. An impact of inflammation on the pharmacokinetics of risperidone was described in two clinical cases (Hefner et al., 2015a) and confirmed in a retrospective comparative study. An increase in the C/D of the risperidone active J o u r n a l P r e -p r o o f moiety has been observed in patients with CRP > 5 mg/L (Hefner et al., 2016) . However, the impact on the pharmacokinetics appears to be lower for risperidone than clozapine (increase in the C/D of 24.2 vs 48.0%). Although safety data were also lacking for risperidone, the clinical impact should be minimal. By contrast, no impact of the CRP value was observed on the pharmacokinetics of quetiapine in the same study. Concerning antidepressant drugs, one retrospective comparative study showed that the CRP concentration was not associated with the pharmacokinetics of citalopram or venlafaxine (Hefner et al., 2015b; Hiemke et al., 2018) . These results confirm a different impact of inflammation on psychotropic drug metabolism depending on the CYP isoform and their respective contribution in the drug clearance. Given that other psychotropic drugs are highly metabolized, an impact of inflammation would be expected for many. However, only scant data are available to support this hypothesis and further studies are needed, including comparative clinical trials. Table 3 ) There is only limited information on the impact of inflammation on the pharmacokinetics of antiepileptics and sedative drugs. In a recent retrospective comparative study, an increase of the C/D of perampanel was observed in epileptic patients with CRP >15 mg/L (Yamamoto et al., 2018) . In a case report on an eight-yearold girl, for whom clobazam (also mainly metabolized by CYP3A4) was co-administered, no impact on the clobazam C/D ratio was observed (Yamamoto et al., 2018) . By contrast, an increase in the metabolism and plasma clearance of valproic acid and phenytoin has been observed in traumatic brain injury patients (Anderson et al., 2007; McKindley et al., 1997) . The authors hypothesized that increased clearance of these drugs could be explained by changes in both pro-and antiinflammatory factors in this population. The impact of inflammation on the pharmacokinetics of midazolam was studied using population pharmacokinetics models on critically ill adult and pediatric populations. A first model was developed based on 26 critically ill Dutch children for whom a decrease in the clearance of J o u r n a l P r e -p r o o f midazolam correlated with disease severity but not CRP levels or leucocyte counts (Vet et al., 2012) . In 2016, a model developed on a larger cohort (83 patients and 523 concentration data points) demonstrated that midazolam clearance was associated with CRP concentration and organ failure but not with IL-6 or TNF-α concentrations (Vet et al., 2016) . The impact of inflammation on the pharmacokinetics of midazolam has also been observed in other populations (full-term neonates and critically ill and healthy adult populations) but not in preterm neonates (Brussee et al., 2018; Franken et al., 2018) . These heterogeneous results highlight the multifactorial aspect of the pharmacokinetic variability of critically ill patients, inflammation likely being one among many factors. Further studies are required, including safety data, to better describe the influence of inflammation on antiepileptic and sedative drug metabolism. Table 3 ) In a study of 13 kidney transplant patients with a urinary tract infection, the concentrations of tacrolimus were higher during treatment with ertapenem than those measured before the infection. Although no biomarkers of inflammation were presented in this study, it can be hypothesized that the increased exposure to tacrolimus may have been related to the episode of acute infection that required antibiotic treatment (Bora et al., 2012) . Consistent with this hypothesis, the Cmin, AUC 0-4 h, Tmax, and Cmax of tacrolimus were reported to be significantly higher during episodes of diarrhea in kidney transplant patients and the Cmin of tacrolimus returned to its previous concentration 2 to 4 weeks later (Sato et al., 2004) . In a meta-analysis that included 66 population pharmacokinetic studies, CRP levels had no significant effect on the interpatient variability of tacrolimus pharmacokinetics, in contrast to CYP3A5 genotypes (Campagne et al., 2019) . However, CRP was investigated in less than 10% of the studies. The tacrolimus Cmin and dose-normalized pharmacokinetic profile were higher for 11 renal transplant recipients experiencing an episode of infectious diarrhea than for nine renal transplant J o u r n a l P r e -p r o o f recipients without diarrhea. Intestinal glycoprotein P activity was decreased by approximately 50% in the patients with diarrhea, suggesting that persistent and severe diarrhea was associated with increased oral bioavailability of tacrolimus. In two cases of pediatric liver transplantation patients treated with either tacrolimus or cyclosporine, the blood concentration of these immunosuppressants nearly doubled 24 hours after an episode of diarrhea with fever. Following the remission of diarrhea, the cyclosporine Cmin returned to the concentrations observed before the diarrheal episode (Maezono et al., 2005) . The Cmax of cyclosporine correlated to those of IL-6 and CRP in six patients who received bone marrow transplants (Chen et al., 1994) . Moreover, the CYP P450-mediated formation of cyclosporine metabolites decreased with inflammation until it was below the limit of detection (Chen et al., 1994) . In a prospective PK study, two children with acute lymphoid leukemia had unexpected elevated sirolimus concentrations after experiencing flu-like symptoms, such as fever and cough, for three days (Mizuno et al., 2019) . The estimated clearance of sirolimus decreased by approximately 40% and 50% for the two patients, necessitating a dose reduction. A similar result was observed in a sirolimus PK study in patients with vascular anomalies (Mizuno et al., 2017) . In patients with documented infection, sirolimus clearance dropped by approximately 50%, requiring a dose reduction. Finally, in renal transplant patients, a higher mycophenolic acid (MPA) AUC 0-9 h (Okamoto et al., 2005) or AUC 0-12 h was observed in patients with infectious disease than in those without (Sommerer et al., 2010) . Table 3 ) A first retrospective study conducted on 128 patients reported a significantly elevated voriconazole Cmin in patients with moderate or severe inflammation (defined by CRP levels between 41-200 mg/L and > 200 mg/L, respectively). This association remained significant after adjustment for J o u r n a l P r e -p r o o f multiple covariables (gender, age, dose, route of administration, liver enzymes, and comedications) (Van Wanrooy et al., 2014) . Such a link between inflammatory status (assessed most often by CRP levels) and voriconazole pharmacokinetics was later confirmed in numerous retrospective cohorts (Dote et al., 2016; Encalada Ventura et al., 2015; Gautier-Veyret et al., 2017; Mafuru et al., 2019; Naito et al., 2015; Niioka et al., 2017; Ventura et al., 2016; Vreugdenhil et al., 2018; Yasu et al., 2017) and in one prospective mono-center study . Moreover, several cases reporting a similar evolution of voriconazole Cmin and CRP levels during longitudinal follow-up illustrate the impact of acute inflammation on voriconazole exposure at the individual level (Truffot et al., 2018; Van Wanrooy et al., 2014; Ventura et al., 2016; Yasu et al., 2017) . Although these studies were heterogeneous in terms of study population (solid organ transplants and hematological patients), biological markers of inflammation (CRP, IL-6, IL-18 levels), and voriconazole pharmacokinetic parameters (Cmin, metabolic ratio), most reported increased voriconazole exposure during acute inflammation (see Table 3 ). Only one study with a limited sample size, performed on 11 children < 12 years of age, did not show any impact of There is little data concerning other triazole antifungals. One prospective study conducted on 55 patients treated with posaconazole did not find any association between the posaconazole Cmin and inflammation, assessed by CRP levels (Märtson et al., 2019) . Similarly, itraconazole exposure did not appear to be related to inflammation, since the unique retrospective cohort published to date did not find any link between the itraconazole Cmin and CRP levels (Naito et al., 2015) . Table 3 ) The results of additional studies also support the hypothesis of the inhibition of DMETs during acute infection. For example, increased concentrations of theophylline during acute viral illness (Chang et al., 1978; Fleetham et al., 1978; Khan & Khan, 2019; Kraemer et al., 1982; Yamaguchi et al., 2000) and of quinine in the early phases of malaria treatment (see review (Morgan et al., 2018) ) have been reported. Very recently, two short reports described higher plasma concentrations of lopinavir in severe COVID-19 patients (Gregoire et al., 2020; Schoergenhofer et al., 2020) compared to those observed in HIV-infected patients and in relation to plasma CRP concentrations (Schoergenhofer et al., 2020) . As for acute inflammation, an inhibitory effect of chronic inflammation on DMETs is expected. However, the contribution of inflammation in the variability of drug exposure is difficult to address in patients with chronic disease due to numerous confounders, such as chronic infection, ageing, physical inactivity, stress, or disturbed sleep, which may be associated with some chronic diseases (Furman et al., 2019) and polymedication. Despite effective antiretroviral therapy, chronic and persistent inflammation is observed in HIVinfected patients. Inflammation-induced pharmacokinetic variability may thus have a significant clinical impact on antiretroviral therapy medication, as efficacy and toxicity are directly associated with drug exposure. Indeed, higher inflammatory biomarker concentrations have been described in HIV patients than uninfected adults and inflammation persists after the suppression of HIV-RNA by antiretroviral therapy (Neuhaus et al., 2010) . Interestingly, a recent study showed that the level of inflammatory markers varies with the level of adherence (Castillo-Mancilla et al., 2016) . CYP activity in HIV-infected patients has been assessed using phenotyping tests. Lower CYP3A4, CYP2D6, and N-acetyl transferase 2 activity (18%, 90%, and 53%, respectively) was observed in 17 HIV-infected adults relative to that in uninfected controls using caffeine, dextromethorphan, and midazolam tests (Jones et al., 2010) . Conversely, no significant difference was found in CYP1A2 activity. In another study using midazolam, dextromethorphan, and digoxin as in vivo phenotyping tests, overall CYP3A activity was approximately 50% lower in HIV-infected patients than in healthy volunteers (30 vs 12 patients, respectively), whereas CYP2D6 activity was unchanged (Jetter et al., 2010 ). An impact of inflammation on the pharmacokinetics of antiretrovirals mainly metabolized by CYP3A, would thus be expected. However, data in the literature are sparse. Decreased maraviroc and elvitegravir clearance has been observed according to inflammatory status (Seifert et al., 2017) . Co-administration of IL-2 with indinavir to nine HIV patients led to an 88% increase in the AUC of indinavir (Piscitelli et al., 1998) . Conversely, no significant correlation was observed between atazanavir clearance and inflammation biomarker concentrations in 107 HIV patients (Venuto et al., 2018) . Yet, in this later study, the effect of inflammation could have been blunted by the presence of the booster ritonavir, which is systematically associated with atazanavir to decrease its clearance. Further studies are thus required to better define the impact of inflammation on the pharmacokinetics, tolerance, and efficacy of antiretroviral treatment. The inflammatory status of HIV-infected patients may also have an impact on the pharmacokinetics of non-antiretroviral drugs. However, no clinical data are currently available and the potential impact is yet to be investigated. Few studies are available for patients with metabolic disorders, but CYP-mediated drug clearance is likely to be reduced in type 2 diabetes. Studies performed on liver tissue from diabetic patients demonstrated a decrease in total CYP content (Sotaniemi et al., 2002) , with diminished expression and activity of CYP3A relative to controls (Dostalek et al., 2011) . In addition, the exposure of the CYP3A substrate nisoldipine is elevated in hypertensive diabetic patients (Marques et al., 2002) and cyclosporine metabolite concentrations are lower in kidney transplant recipients with diabetes mellitus (Akhlaghi et al., 2012) than in controls. Although these data are concordant, the role of inflammation in such CYP downregulation in diabetes has never been investigated. Recently, a prospective study using a cocktail of probe drugs showed a decrease of approximately 38, 46, and 45% of the mean metabolic activity for CYP3A, 2C19, and 2B6, respectively, in 38 patients with type 2 diabetes relative to 35 controls (Gravel et al., 2019) . Considering all diabetic and nondiabetic subjects, the IL-6 concentration significantly negatively correlated with the activities of CYP2B6, 2C19, and 3A in univariate analysis. Moreover, IFN-γ and TNF-α concentrations were identified as independent determinants of CYP2C19 and 2B6 activity (Gravel et al., 2019) . These data all suggest that the inhibition of CYP-mediated drug clearance in type 2 diabetes may be related to inflammatory processes. However, these findings must to be confirmed, as the controls of these studies were often not well matched in terms of age, sex, or body mass index (Akhlaghi et al., 2012; Gravel et al., 2019; Marques et al., 2002) . Nonalcoholic fatty-liver disease (NAFLD) is associated with alterations of DMET expression and activity in experimental murine models and patients (see review (Cobbina & Akhlaghi, 2017) ). This translates into increased midazolam exposure and an increased AUC of the glucuronide J o u r n a l P r e -p r o o f metabolites of morphine and acetaminophen via the upregulation of the MRP3 efflux transporter. However, these results are limited and sometimes conflicting and need to be further investigated. The principal consequence of CKD on drug pharmacokinetics is a decrease in renal clearance. However, an impact of CKD on non-renal clearance has also been observed in many studies. Decreased CYP2C11, 3A1, 3A2, and N-acetyl transferase activity has been observed in nonclinical studies, whereas no modification was observed in CYP 1A1, 2B1, 2C6, and UDP-GT activity (Naud et al., 2012) . In clinical studies, decreased non-renal clearance has been observed for numerous drug substrates of metabolizing enzymes (Nolin, 2008) . Uremic factors (such as parathyroid hormone) that accumulate in end stage renal disease were identified as the main factors that contribute to varying non-renal clearance. Indeed, uremic factors decrease the mRNA expression and thus activity of drug-metabolism enzymes (Naud et al., 2012) . As a systemic inflammatory response is observed in CKD patients (Stenvinkel, 2006) , inflammatory factors may also be involved in reduced CYP activity. However, data are still lacking to accurately describe the impact of each factor in this multifactorial change. The impact of inflammation on CKD patients has been independently investigated in only one study, using alprazolam as a probe drug for CYP3A4 activity (Molanaei et al., 2018) . The ratio of alprazolam to 4-hydroxyalprazolam correlated with CRP concentrations in 26 hemodialysis patients, suggesting the downregulation of CYP3A4 activity by inflammation. CRP concentrations positively correlate with weight loss, anorexia-cachexia syndrome, extent of disease, and recurrence in advanced cancer (Mahmoud & Rivera, 2002) . Rivory et al. evaluated hepatic CYP3A activity using the phenotypic 14 C-erythromycin breath test in cancer patients with CRP > 10 mg/L. They showed a mean 30% decrease in CYP3A activity relative to that in patients without an acute-phase response (Rivory et al., 2002) . In patients with advanced cancer, docetaxel pharmacokinetics were the only predictive factor for hematological toxicity. The odds of severe J o u r n a l P r e -p r o o f hematological toxicity were approximately nine-fold higher for patients with reduced docetaxel clearance. The odds of non-hematological toxicity were approximately three-fold higher for patients with elevated orosomucoid or CRP concentrations (> 1.5 g/L and > 10 mg/L, respectively) (Charles et al., 2006) . Studies performed in patients with rheumatoid arthritis or Crohn's disease support the hypothesis that inflammation contributes to the inhibition of drug metabolism. For example, higher exposure of verapamil in patients suffering from rheumatoid arthritis (Mayo et al., 2000) or Crohn's disease (Sanaee et al., 2011) than controls has been reported. In addition, rheumatoid arthritis patients exhibit higher plasma concentrations of simvastatin, another CYP450 substrate (Schmitt et al., 2011) and lower plasma concentrations of 4-ßhydroxycholesterol, an endogenous CYP3A4 metabolite (Wollmann et al., 2017) . CYP3A4 activity has been shown to correlate with proinflammatory cytokine levels, especially those of IL-1ra, IL-6, and CXCL8 (Wollmann et al., 2018) . In addition, the central role of IL-6 in the inhibition of CYP clearance in rheumatoid arthritis has been shown in clinical trials evaluating monoclonal antibodies targeting IL-6 ( Schmitt et al., 2011; Zhuang et al., 2015) . Indeed, these studies all showed that pharmacological inhibition of IL-6 restored CYP3A activity, with a significant decrease in simvastatin exposure of approximately 55 and 57% after the administration of sarilumab In chronic liver disease, most studies have focused on the impact of liver impairment on pharmacokinetics and inflammation is thus difficult to investigate as an independent factor of pharmacokinetic variability. UDP-GT mRNA levels were compared between liver biopsies of patients with low and high fibrosis or inflammation scores. Lower hepatic UDP-GT mRNA levels were observed in biopsies from patients with a high inflammation score, but not in those from patients with a high degree of fibrosis (Congiu et al., 2002) . activity was also observed in 41 chronic hepatitis B patients (Wang et al., 2010) . Inflammation is observed during liver regeneration in living-donor liver transplantation and could affect drug metabolism in both donors and recipients (Li et al., 2016) . However, no data are currently available to confirm this hypothesis. Inflammation reduces clearance by certain CYP and phase 2 enzymes, translating into the phenoconversion of intra-individual metabolic capacities. In particular, phenoconversion for extensive-metabolizer patients results in the change of a genotypic extensive metabolizer into a J o u r n a l P r e -p r o o f phenotypic poor metabolizer, leading to genotype-phenotype mismatches and an unpredictable increase in pharmacokinetic exposure to drugs that are DMET substrates, a drastic decrease in pharmacokinetic exposure to the corresponding metabolites, or reduced activity of pro-drugs. The clinical significance in terms of efficacy and safety of phenoconversion depends on whether the drug and/or its metabolites support the pharmacodynamic activity and their therapeutic index. In addition to extrinsic factors, including drug-drug interactions (see previous review (Shah & Smith, 2015) ) or food/drug interactions, inflammation is an important intrinsic factor that can cause metabolic phenoconversion. Thus, unlike genotype, the pharmacokinetic phenotype of a subject is dynamic and inflammation-induced phenoconversion can transitorily blunt the pharmacogenotype. Tables 2 and 3 The clinical consequences of inflammation-induced metabolic conversion are heterogenous. Overexposure to theophylline or clozapine in association with acute inflammatory episodes has been associated with concomitant clinical signs of drug-related toxicity, whereas the immediate clinical consequences of increased exposure to voriconazole, tacrolimus, or risperidone associated with inflammation have not been documented (see table 3 ). These data confirm that the inhibitory effect of inflammation on CYP may vary according to the CYP subfamily as previously discussed. In vitro hepatocyte experiments have shown that the potency of IL-6 to inhibit CYP was the strongest towards CYP1A2 relative to other CYPs (Dickmann et al., 2011) . Since theophylline and clozapine are CYP1A2 substrates, the particular potency of IL-6 to inhibit CYP1A2 could explain the onset of theophylline or clozapine toxicity during acute episodes of inflammation. Although the metabolic phenoconversion induced by inflammation may not be associated with short-term clinical signs of toxicity for other drugs (tacrolimus, voriconazole, risperidone), acute inflammation can also contribute to the increase in intra-individual variability of drugs that are CYP substrates, possibly leading to deleterious long-term consequences. For example, increased intraindividual variability of the tacrolimus blood Cmin is associated with a poorer clinical outcome in J o u r n a l P r e -p r o o f hepatic transplant patients (Rayar et al., 2018) . Moreover, it should also be kept in mind that total plasma drug concentration (free concentration + bound concentration) are measured during TDM or in most clinical studies (see Table 3 ). Certain drugs have strong binding affinity (>98%) for orosomucoid, the concentration of which is increased during acute inflammation (see Table 1 ). Thus, in a context of severe inflammation, the increased plasma total concentration of a drug highly bound to orosomucoid mainly reflects increased bound concentration. For example, correlations between orosomucoid concentration and risperidone+9-OH risperidone or lopinavir exposures have been described in a schizophrenic patient with pneumonia (Helland et al., 2018) or in patients with severe HIV disease respectively (Ofotokun et al., 2011) . Since the bound concentration of a drug do not supports its pharmacological activity, this could contribute to explain the absence of clinical signs of toxicity in some situations, although a total overexposure is measured (Helland et al., 2018) . systematically recommended. Pharmacologists should also take into consideration the pharmacokinetic properties of the drug, including its binding to orosomucoid, the importance of the different metabolic pathways involved in its clearance, and its terminal elimination half-life. For drugs highly bound to plasma proteins, a dose reduction could sometimes lead to loss of efficacy. But if adverse effects are observed, pharmacologists can suggest the brief discontinuation of treatment rather than dose reduction to avoid secondary underexposure upon the resolution of inflammation. The resolution of an acute inflammatory episode is a complex physiological process, depending on the trigger of inflammation, and no study has investigated the duration of its resolution. This lack of data is a strong limitation for proposing dose reduction of DMET substrates to avoid consequent pharmacokinetic underexposure, notably for drugs with a narrow therapeutic window. Several case reports have suggested the repression of DMET inhibition at the resolution of the inflammatory episode, leading to reduced exposure of the DMET substrate in the context of chronic inflammation. The tacrolimus blood concentration decreased in two HCV-infected and livertransplanted patients during treatment with daclastavir/sofosbuvir/ribavirin (Smolders et al., 2017) . Since a direct drug/drug interaction between the direct-acting antivirals, ribavirin and tacrolimus, could be excluded, this study suggested that the unexpected observed decrease in the tacrolimus blood concentration when the sustained virological response was achieved could have been the consequence of the resolution of the HCV infection (Smolders et al., 2017) . Treatment of rheumatoid arthritis patients with the monoclonal antihuman IL-6 receptor antibody tocilizumab (Schmitt et al., 2011) or sarilumab normalized plasma CRP levels within one week after infusion and reduced simvastatin plasma exposure by 43 and 54%, respectively. These data suggest that blockade of the IL-6-dependent pathway reversed the suppression of CYP3A4 activity induced by inflammation and confirm the key role of IL-6 in the downregulation of CYP activity. Conversely, the antihuman IL-17A monoclonal antibody sekukinumab failed to modify the pharmacokinetic profile of midazolam in patients with moderate to severe psoriasis (Bruin et al., 2019) . Similarly, the antihuman IL-23 antibody risankizumab did not affect the in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A in patients with moderate plaque psoriasis (Khatri et al., 2019) . However, systemic inflammation was minimal in these study populations. drugs over the first week of treatment at least and, if underexposure is detected, increasing the dose so as to avoid loss of efficacy. The impact of chronic or acute inflammation on drug pharmacokinetics has been studied using population pharmacokinetic models in only a few studies including inflammation factors as covariates. However, this methodology is probably a good approach to evaluate the impact of inflammation on pharmacokinetics and metabolism as an independent factor of variability. As previously described, inflammation is one of the many factors (demographic, genetic, pathological, etc.) that influences drug pharmacokinetics. Pharmacokinetic population studies could allow identification of the contribution of inflammation in interindividual variability relative to that of other covariates, such as disease severity or glomerular filtration rate. Studying the relationship between inflammation and drug pharmacokinetics could also be helpful in adapting treatment, taking into account the limitation of the large intra-individual variability observed due to the inflammation status. studies as potential covariates, like renal or hepatic function biomarkers, especially for highly metabolized drugs. Compelling evidence suggests that inflammation is a major regulator of DMETs and thereby contributes to intra-and interindividual pharmacokinetic variability of DMET substrates. The inhibitory effect of inflammation likely depends on its severity and the contribution of DMETs in the intrinsic clearance of a drug. However, the concentrations of the inflammatory biomarkers that inhibit the activity of each DMET are yet to be determined. This is essential in preventing overexposure to drugs that are DMET substrates, particularly concerning the ageing population and patients with a high prevalence of inflammatory comorbidities, including acute infections, and J o u r n a l P r e -p r o o f requires further studies. Studies aiming to investigate the genotype-predicted phenotype should also take into account the inflammatory status of patients to avoid misinterpretation, as the phenoconversion induced by inflammation may blunt the impact of genetic polymorphisms on drug pharmacokinetics and responses. As for genotype, demographic data, drug-drug interactions, and inflammatory biomarkers should be systematically taken into consideration for the personalization of drug treatment. The authors state that the work described has not been published previously, that it is not under consideration for publication elsewhere, that its submission is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out. If accepted, it will not be published elsewhere in the same form, in English or in any other language, without the written consent of the copyright-holder. The authors state that the manuscript has not been published and is not under consideration for publication anywhere. All authors state they have no actual or potential conflict of interest including any financial, personal or other relationships with individuals or organizations within three years of initiating the work that could inappropriately influence, or be perceived to influence, the study design or data interpretation. This work was supported by no financial funding. Scheme of the inhibitory influence of inflammation on drug-metabolizing enzyme and transporter (DMET) activity, leading to overexposure to drugs that are DMET substrates and have a narrow therapeutic index. Pathogen-associated molecular patterns or damage-associated molecular patterns stimulate pro-inflammatory cytokine pathways, leading to transcriptional and posttranscriptional changes in DMETs. Transcriptional mechanisms involve NF-B activation, which inhibits the heterodimerization of nuclear retinoid x receptor (RXR)-α to other constitutive nuclear receptors (NR) (1), thus inhibiting DMET transcription (2) (under the magnifying glass). Non transcriptional mechanisms involve the direct inhibition of DMET by NO and the induction of proteasome-dependent CYP3A4 inhibition by NO. Finally, epigenetic changes, such as DNA methylation in response to inflammation, contribute to reduced DMET activity (underthe magnifying glass). NR: nuclear receptor, including the peroxisome proliferator activating receptor, pregnane X receptor, retinoid X receptor-α, and constitutive androstane receptor. Solid lines indicate activation and dotted lines indicate inhibition. (Hiemke et al., 2018) ; ** Voriconazole therapeutic reference range : 1-4 mg/L. Figure 1 Effect of interleukin-6 neutralization on CYP3A11 and metallothionein-1/2 expressions in arthritic mouse liver Pharmacokinetics of quinine in African patients with acute falciparum malaria The liver in sepsis: patterns of response and injury Unexpected overdose blood concentration of tacrolimus: Keep in mind the role of inflammation Drug interaction between tacrolimus and ertapenem in renal transplantation recipients Secukinumab Treatment Does Not Alter the Pharmacokinetics of the Cytochrome P450 3A4 Substrate Midazolam in Patients With Moderate to Severe Psoriasis Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure Clinical Pharmacokinetics of Mycophenolate Mofetil Population Pharmacokinetics of Tacrolimus in Transplant Recipients: What Did We Learn About Sources of Interindividual Variabilities Role of nitric oxide in the cytokine-mediated regulation of cytochrome P-450 Suboptimal Adherence to Combination Antiretroviral Therapy Is Associated With Higher Levels of Inflammation Despite HIV Suppression Regulation of Hepatic Cytochrome P450 Expression in Mice with Intestinal or Systemic Infections of Citrobacter rodentium TLR4-dependent andindependent regulation of hepatic cytochrome P450 in mice with chemically induced inflammatory bowel disease Altered theophylline pharmacokinetics during acute respiratory viral illness Predicting the toxicity of weekly docetaxel in advanced cancer Non-alcoholic fatty liver disease (NAFLD) -pathogenesis, classification, and effect on drug metabolizing enzymes and transporters UDP glucuronosyltransferase mRNA levels in human liver disease. Drug Metabolism and Disposition Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report The end of AIDS: HIV infection as a chronic disease TNF-α level affects etanercept clearance: TNF-α concentration as a new correction factor of allometric scaling to predict individual etanercept clearances in patients with ankylosing spondylitis Modulation of cytochrome P450 2A5 activity by lipopolysaccharide: low-dose effects and nonmonotonic dose-response relationship Murine collagen antibody induced arthritis (CAIA) and primary mouse hepatocyte culture as models to study cytochrome P450 suppression Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in J o u r n a l P r e -p r o o f human hepatocyte culture Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus A retrospective analysis of patient-specific factors on voriconazole clearance Influence of inflammation on voriconazole metabolism Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations A puzzling case of increased serum clozapine levels in a patient with inflammation and infection Theophylline pharmacokinetics and respiratory infections Population pharmacodynamic modelling of midazolam induced sedation in terminally ill adult patients Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect? Plasma levels of TNF-alpha and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure Chronic inflammation in the etiology of disease across the life span Acute-phase proteins and other systemic responses to inflammation Pharmacogenetics may influence the impact of inflammation on voriconazole trough concentrations Inflammation is a potential risk factor of voriconazole overdose in hematological patients Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters Helicobacter pylori infection is associated with greater impairment of cytochrome P-450 liver metabolic activity in anti-HCV positive cirrhotic patients Modulation of CYP450 activities in patients with type 2 diabetes Lopinavir pharmacokinetics in COVID-19 patients Disease-drug interaction: Reduced response to propranolol despite increased concentration in the rat with inflammation Effects of Diabetes Mellitus on the Disposition of Tofacitinib, a Janus Kinase Inhibitor, in Rats Toxic rise of clozapine plasma concentrations in relation to inflammation Analysis of DNA methylation landscape reveals the roles of DNA methylation in the regulation of drug metabolizing enzymes Elevated risperidone serum concentrations during acute inflammation, two cases Retrospective pilot study for analysis of antidepressant serum concentrations of citalopram and venlafaxine during inflammation Inflammation and psychotropic drugs: The relationship between C-reactive protein and antipsychotic drug levels Systemic Inflammation Complicates the Interpretation of Therapeutic Drug Monitoring of Risperidone Epigenetic regulation of MDR1 gene through post-translational histone modifications in prostate cancer Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update Epigenetic mechanisms of importance for drug treatment Toxic clozapine serum levels during acute urinary tract infection: a case report Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients? Variability in drug metabolizing enzyme activity in HIV-infected patients Screening of nonsteroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDPglucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS Extrahepatic cancer represses hepatic drug metabolism via interleukin (IL)-6 signalling The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling Immunometabolism and atherosclerosis: perspectives and clinical significance: a position paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology Effect of tildrakizumab (MK-3222), a high affinity, selective anti-IL23p19 monoclonal antibody, on cytochrome P450 metabolism in subjects with moderate to severe psoriasis Rare Case of Theophylline Toxicity due to Influenza A Infection in an Adult With Asthma Lack of Effect of 12-Week Treatment with Risankizumab on the Pharmacokinetics of Cytochrome P450 Probe Substrates in Patients with Moderate to Severe Chronic Plaque Psoriasis Selective role for tumor necrosis factor-α, but not interleukin-1 or Kupffer cells, in down-regulation of CYP3A11 and CYP3A25 in livers of mice infected with a noninvasive intestinal pathogen Combination of CYP2C19 genotype with non-genetic factors evoking phenoconversion improves phenotype prediction Population pharmacokinetics of quinine in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda Altered theophylline clearance during an influenza B outbreak Disposition of Posaconazole following Single-Dose Oral Administration in Healthy Subjects MiR-155 and other microRNAs downregulate drug metabolizing cytochromes P450 in inflammation Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity Dual Mechanisms of CYP3A Protein Regulation by Proinflammatory Cytokine Stimulation in Primary Hepatocyte Cultures Nitric oxide-regulated proteolysis of human CYP2B6 via the ubiquitin-proteasome system Disease-Drug Interaction of Sarilumab and Simvastatin in Patients with Rheumatoid Arthritis activity and assimilation of tacrolimus in persistent diarrhea Pharmacokinetics of drugs in adult living donor liver transplant patients: regulatory factors and observations based on studies in animals and humans Effect of early phase adjuvant arthritis on hepatic P450 enzymes and pharmacokinetics of verapamil: an alternative approach to the use of an animal model of inflammation for pharmacokinetic studies The effect of infliximab on hepatic cytochrome P450 and pharmacokinetics of verapamil in rats with pre-adjuvant arthritis: a drug-disease and drugdrug interaction Elevated blood concentrations of calcineurin inhibitors during diarrheal episode in pediatric liver transplant recipients: involvement of the suppression of intestinal cytochrome P450 3A and P-glycoprotein The Influence of Proinflammatory Cytokines on Voriconazole Trough Concentration in Patients With Different Forms of Hematologic Disorders The role of C-reactive protein as a prognostic indicator in advanced cancer Dynamic and kinetic disposition of nisoldipine enantiomers in hypertensive patients presenting with type-2 diabetes mellitus Posaconazole trough concentrations are not influenced by inflammation: A prospective study Down-regulation of hepatic cytochrome P450 enzymes in rats with trinitrobenzene sulfonic acid-induced colitis Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis Effect of acute phase response on phenytoin metabolism in neurotrauma patients Selective and cytokine-dependent regulation of hepatic transporters and bile acid homeostasis during infectious colitis in mice A non-lethal malarial infection results in reduced drug metabolizing enzyme expression and drug clearance in mice Hepatic cytochrome P450s, phase II enzymes and nuclear receptors are downregulated in a Th2 environment during Schistosoma mansoni infection Developmental pharmacokinetics of sirolimus: Implications for precision dosing in neonates and infants with complicated vascular anomalies Significant effect of infection and food intake on sirolimus pharmacokinetics and exposure in pediatric patients with acute lymphoblastic leukemia Inflammation down-regulates CYP3A4-catalysed drug metabolism in hemodialysis patients Influence of chronic hepatitis C infection on cytochrome P450 3A4 activity using midazolam as an in vivo probe substrate Regulation of Cytochromes P450 During Inflammation and Infection Regulation of Drug-Metabolizing Enzymes and Drug Metabolism by Inflammatory Responses Physiological Regulation of Drug Metabolism and Transport: Pregnancy, Microbiome, Inflammation, Infection, and Fasting Effect of lipopolysaccharide on the xenobiotic-induced expression and activity of hepatic cytochrome P450 in mice Impact of inflammation and concomitant glucocorticoid administration on plasma concentration of triazole antifungals in immunocompromised patients Points of control in inflammation Current understanding of drug disposition in kidney disease A guiding map for inflammation Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection Relationship between the CYP2C19 Phenotype Using the Voriconazole-to-Voriconazole N -Oxide Plasma Concentration Ratio and Demographic and Clinical Characteristics of Japanese Patients with Different CYP2C19 Genotypes Altered nonrenal drug clearance in ESRD. Current Opinion in Nephrology and Hypertension Selective effects of a therapeutic protein targeting tumor necrosis factor-alpha on cytochrome P450 regulation during infectious colitis: Implications for disease-dependent drug-drug interactions Modulation of hepatic cytochrome P450s by Citrobacter rodentium infection in interleukin-6-and interferon-{gamma}-null mice Immune activation mediated change in alpha-1-acid glycoprotein: impact on total and free lopinavir plasma exposure Therapeutic drug monitoring of mycophenolic acid in renal transplant recipients Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De-Escalation in Adults With Inflammatory Bowel Diseases Toxic clozapine serum levels during inflammatory reactions Alteration in indinavir clearance during interleukin-2 infusions in patients infected with the human immunodeficiency virus Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution A study of the factors affecting the metabolic clearance of quinine in malaria Effect of influenza vaccination on serum clozapine and its main metabolite concentrations in patients with schizophrenia Tacrolimus Concentrations Measured in Excreted Bile in Liver Transplant Recipients: The STABILE Study Hepatic cytochrome P450 gene regulation during endotoxin-induced inflammation in nuclear receptor knockout mice Hepatic and renal cytochrome p450 gene regulation during citrobacter rodentium infection in wild-type and toll-like receptor 4 mutant mice Expression of UDPglucuronosyltransferase isoform mRNAs during inflammation and infection in mouse liver and kidney Inflammation-Associated MicroRNA-130b Down-Regulates Cytochrome P450 Activities and Directly Targets CYP2C9 Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response Two cases of high serum clozapine concentrations occurring during inflammation in Chinese patients Levels Were Elevated during Infections in a Retrospective Review of 131 Beijing Hospital In-Patients with More than 24,000 Days of Clozapine Treatment Serum quinine concentrations following the initial dose in children with falciparum malaria Association of DNA Methylation with Acute Mania and Inflammatory Markers Changes in expression of hepatic cytochrome P450 subfamily enzymes during development of adjuvant-induced arthritis in rats Drug-disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity Severe elevations of FK506 blood concentration due to diarrhea in renal transplant recipients Disease-Drug-Drug Interaction Involving Tocilizumab and Simvastatin in Patients With Rheumatoid Arthritis Pharmacokinetics of Lopinavir and Ritonavir in Patients Hospitalized With Coronavirus Disease 2019 (COVID-19) Inflammation and pharmacokinetics: potential implications for HIV-infection Down-regulation of cytochrome P450 mRNAs and proteins in mice lacking a functional NOS2 gene Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine Impact of Interleukin-6 on Drug-Metabolizing Enzymes and Transporters in Intestinal Cells Decreased tacrolimus plasma concentrations during HCV therapy: a drugdrug interaction or is there an alternative explanation? Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients Diabetes and elimination of antipyrine in man: an analysis of 298 patients classified by type of diabetes, age, sex, duration of disease and liver involvement Inflammation in end-stage renal disease: the hidden enemy Disposition of oral quinine in acute falciparum malaria NF-kappaB: a key role in inflammatory diseases Hepatic Cytochrome P450 Activity and Nitric Oxide Production During Multiple Ovalbumin Challenges The effect of inflammation on voriconazole trough concentrations in children Optimization of initial tacrolimus dose using pharmacogenetic testing Quinine disposition during malaria and during induced fever Inhibition of Voriconazole Metabolism by Meropenem: A Role for Inflammation? Personalized Drug Dosage -Closing the Loop Inflammation is associated with voriconazole trough J o u r n a l P r e -p r o o f concentrations Longitudinal Analysis of the Effect of Inflammation on Voriconazole Inflammation investigated as a source of pharmacokinetic variability of atazanavir in AIDS Clinical Trials Group protocol A5224s Voriconazole metabolism is influenced by severe inflammation: a prospective study Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children Pediatric Critical Care Medicine: A Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Moderate correlation between systemic IL-6 responses and CRP with trough concentrations of voriconazole Activity of sulfotransferase 1A1 is dramatically upregulated in patients with hepatocellular carcinoma J o u r n a l P r e -p r o o f secondary to chronic hepatitis B virus infection Quinine pharmacokinetics and toxicity in cerebral and uncomplicated Falciparum malaria Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis 4 β -Hydroxycholesterol Level in Patients With Rheumatoid Arthritis Before vs. After Initiation of bDMARDs and Correlation With Inflammatory State: 4 β OHC Level in Patients With RA Before vs. After Initiation of bDMARDs The regulation of drug-metabolizing enzymes and membrane transporters by inflammation: Evidences in inflammatory diseases and age-related disorders Higher incidence of elevated body temperature or increased C-reactive protein level in asthmatic children showing transient reduction of theophylline metabolism Influence of Inflammation on the Pharmacokinetics of Perampanel Pregnane X receptor is required for interleukin-6-mediated down-regulation of cytochrome P450 3A4 in human hepatocytes Enhanced Platelet Response to Clopidogrel in Zucker Diabetic Fatty Rats due to Impaired Clopidogrel Inactivation by Carboxylesterase 1 and Increased Exposure to Active Metabolite Serum C-reactive protein levels affect the plasma voriconazole trough levels in allogeneic hematopoietic cell transplant recipients Changes in the expression of cytochromes P450 and nuclear receptors in the liver of genetically diabetic db/db mice MicroRNA hsa-miR-370-3p suppresses the expression and induction of CYP2D6 by facilitating mRNA degradation Diet-induced obese alters the expression and function of hepatic drug-metabolizing enzymes and transporters in rats Epigenetic regulation of the innate immune response to infection The authors thank Pr Michel Tod and Pr Pierre Oliver Girodet for their expertise on the scientific content of the manuscript and Martine Micheloni for infographic help.