THE BEHAVIOR OF SOME AROMATIC ESTERS OF THERAPEUTIC VALUE IN METABOLISM BY RALPH LESTER HORST A.B. Nebraska Wesleyan University, 1918 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN CHEMISTRY IN THE GRADUATE SCHOOL OF THE UNIVERSITY OF ILLINOIS, 1922 URBANA, ILLINOIS Digitized by the Internet Archive in 2015 https://archive.org/details/behaviorofsomearOOhors UNIVERSITY OF ILLINOIS THE GRADUATE SCHOOL May 39 1 HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY. Ralph Lest er Korat entitled. The Beh avior of Some Aromatic Este rs of Therapeutic Value, in Metabolism. BE ACCEPTED AS FULFILLING THIS PART OF THE REQUIREMENTS FOR THE DEGREE of Master of Scienc e In Charge of Thesis Head of Department Recommendation concurred in* Committee on Final Examination* Required for doctor’s degree hut not for master’s ■ ■ .... Acknowledgement . The writer w ishes to take this opportunity to express his appreciation of the guidance and help given by Dr. H.B. Lewis in the preparation of this thesis. fable of Contents page I. Introduction 1 II. Historical. 1 IIL Experimental 4 IV. Discussion 7 V Tables 10 V. General Conclusion 9 VI. Summary 9 VLL Bibliography • 22 . 1 I. Introduction In the previous studies of benzyl alcohol and its esters, tv/o chief purposes have been in mind. I. The uses and action of benzyl alcohol as a local anesthetic. II. The physiological action of the benzyl esters. Since the use of this alcohol and its esters is increasing in therapeutical practices, it was considered of importance to study the behavior of these compounds in metabolism in the animal body. II. Historical In 1914, Filippi, (1), an Italian investigator, found that benzyl alcohol caused sleepiness, a paralysis, and a lowering of the body temperature. Ilacht and his co-workers have made many studies on this alco- hol and its esters and it is to him that we owe most of our know- ledge of their action. His first work was carried out in 1918 (2) with the alcohol. He found that it is a powerful local anesthetic and used it with great success in the treatment of abscesses, extraction of teeth and skin grafting. A 1 c Jo aqueous solution was used. He also used it /as a local anesthetic in subcutaneous and inti®, muscular injec- tions. He found that it had an irritating effect upon the skin, but that it was an antiseptic and the wound healed well. Eucaine cocaine and novocaine did not have antiseptic properties. (4) Ilacht, Satani , and Schwartz (5) even stated that benzyl alcohol was antiseptic and germicidal to gonococcus, staphylococcus and B. 6oli. Ilacht also found that it ?/as very useful as a local anesthetic > . : . '• 2 . in genito-ur inary work. (6) Sollman (7) studied its anesthetic ac- tion upon various types of mucous membrane and found it to he weak- er in its action than cocaine. Voegtlin and Livingstone (8) injected it in regions near the spinal cord and in this way anesthetized the posterior part of the body. They also obtained a lowering of blood pressure and a depres sion of respiration. Macht (6) found that benzyl benzoate and benzyl acetate (2) both had the same ant i spasmodic or anesthetic effect upon muscles as papaverine, and had a lower toxicity. He stated that they were easily metabolized and considers the action of papaverine to be due to the benzyl group present. Both could be used in excessive per- istalsis. He found the acetate bo be of the higher toxicity due to its bein^ absorbed more rapidly. The benzoate was found to be useful in spasmodic dysmenorrhea, spastic conditions of the intes- tine and stomach, threatened abortion and renal and biliary colic. It also had a depressing action upon blood pressure. Mason (9) also found this. Heller and Steinfield (10) found that the injected benzoate had no toxic action upon th6 leucocytes. Ilielson and Higgins ( n) injected the cinnamate and benzoate. Both caused a relaxation of the intestine and a lowering of blood pressure, also a venous coloration of the arterial blood. Later (12) they used other benzyl esters and they all produced the same general effect. -They considered the action to be due to the hydrol ysis Of the ester to benzyl alcohol. In simple esters the action was proportional to the rate of hydrolysis. In substituted esters as the salicylate and acetyl-salicylate the action was more rapid. 3. Macht (13) also studied the action of benzyl succinate and found it to have the sarae toxicity as the benzoate, but the action as an ant spasmodic was milder and longer in duration due to the slow- er breakdown of the ester. Volwiler and Vliet (14) worked with various benzyl esters and stated that the antispasmodic action was due to the nucleus ring. They found the rate of hydrolysis with ZOH to increase in the fol- lowing order : salicylate, benzoate, stearate, cinnamate, acetate, succinate and fumarate. Shonle and Row (15) prepared a variety of benzyl esters of the saturated and unsaturated higher fatty acids. 'They found them to be insoluble in water, but readily soluble in chloroform, ether and benzene. Because of their low solubility they had neither local anesthetic effect nor irritant action upon mucous membrane. Clin- ical tests demonstrated their antispasmodic action in asthma, dys- menorrhea, high blood pressure, pylorospasm and spastic constipation. Although not hydrolyzed by steam these esters were readily split by lipase. If aromatic acids were substituted for the aliphatic, the hydrolysis was much slower. The laurate, myristate., palmitate , stearate, oleate, lactate and the m- and p- arr,ino benzoates were prepared. Of these only the m- and p- ar ino benzoates had local anesthetic properties. The work of these investigators shows the therapeutic value of benzyl alcohol and its esters as local antiseptics and as antispas- modics . The work on the metabolism of benzyl alcohol and its esters is very limited. Macht (2) investigated the fate of the acetate and the benzoate 4 in the body and found that they were in a large measure excreted as hippuric acid in the urine. This transformation of these esters into hippuric acid he considered as involving a transition from the esters through the alcohol. In rabbits this transformation was more rapid than in the dog. His work on the alcohol would also in- dicate that it is in a large measure excreted in the urine in the form of hippuric acid. III. Experimental . This work was carried out in order to study the behavior of benzyl succinate in metabolism, as compared with other benzyl enters and 30dium benzoate, making use of the increased elimination of hippuric and free benzoic acid in the urine as a guide to the met- abolism of the compound. The purity of the succinate was determined by saponification with a known amount of KOH. It was found to be 99.4-100$ benzyl succinate . It was first decided to study the action of hog liver lipase upon this ester, a di-carboxylic ester, as compare! with a mono-car- boxylic ester, ethyl propionate, by the method which Christman and Lewis (16) used in their lipase studies. A glycerol extract of hog liver was made within one hour after the death of the animal. Since benzyl succinate is insoluble in water and does not melt at body temperature, emulsions with dextrin and acacia were tried with continuous shaking in a machine, but no splitting of the ester by the lipase, worthy of mention could be obtained. This seemed to be due to a poor emulsion as the enzyme was found to be very active. Attention was then turned to the administration of the ester ■ . ■ ’ 5 . per os and studying its splitting in the animal body. The ester might have been split to the alcohol which could have been elimina- ted in the urine as such or oxidized and eliminated as hippuric acid, or passed through into the urine unchanged. It was decided to use the method of Kingsbury and Swanson (16) for the determination of hippuric acid in the urine and thereby estimate the amount of ester, which was split, oxidized and elim- inated as free benzoic or as hippuric acid. This method is really a determination of total benzoic acid or free benzoic plus hippuric acid. From the work of others this was known to be a very accurate method. It consists of the hydrolysis of the hippuric acid with sodium hydroxide, oxidation of interfering substances with nitric acid and potassium permanganate^ extract ion of the benzoic acid with chloroform, and titration of this extract with standard sodium eth- ylate . There is a possibility her6 that any free benzyl ester in the urine would be hydrolyzed and the alcohol oxidized to benzoic acid by the nitric acid and potassium: permanganate and titrated as ben- zoic acid present in the urine originally. In order to determine whether this happens, this method was used upon a known amount of the ester. A negligible amount was changed to benzoic acid in the procedure. (Table I). If part of the ester is hydrolyzed to alcohol and eliminated as such in the urine, there is a possibility of this being oxidized, in this procedure, to benzoic acid and determined as benzoic acid originally present. This method was also tested on urine contain- ing a known amount of the alcohol. ITo appreciable oxidation of the alcohol was obtained in this procedure. (Table Ilj. .»U • • • • ■ « 5 • For the determination of free benzoic acid or benzoates in the urine, the method of P.aiziss and Dubin (17) was used. This invol- ves acidification with a small amount of nitric acid and extraction of the benzoic acid with toluene. Since benzyl succinate is also soluble in toluene, it was decided to determine its presence in the urine by saponification of the neutralized toluene extract with ex- cess sodium ethylate and titration of the excess. The complete procedure to be used was carried out upon a urine containing a known amount of added sodium hippurate, sodium benzo- ate and benzyl succinate dissolved in alcohol. An aliquot was used for the determination of total benzoic acid or hippuric acid plus free benzoic acid from the benzoate added. A good recovery of these two compounds was obtained. Another aliquot was tested for free benzoic acid and after the neutralization of the toluene extract, an excess of sodium ethylate was add6d and this refluxed to saponify the ester. The remaining alkali was titrated and the amount of saponifiable matter determined A good recovery of the sodium benzoate and benzyl succinate was ob- tained. (Table III). In the following experiments rabbits fed a standard diet were used as the experimental animals. A weighed amount of the alcohol, ester or sodium benzoate was administered per os, the bladder emp- tied at various intervals and the urine analyzed. Benzyl succinate melts at 45* C. and was given melted and emul- sified with milk as f -as possible. Benzyl alcohol and the ace- tate, being liquids, were well mixed with milk and given in that form. Sodium benzoate was dissolved in water and given, mixed with a small amount of milk. The normal diet used was 10 grams of sucrose in 150 cubic cen- 7 timeters of milk in the first expert) ents with 10-15 grains of oats in addition in the later work, was flie urin6 collected as indicated. Three days on a normal diet elapsed between the feeding of the compounds, but this was varied later as shown in the tables. The number of cubic-centimeters of standard sodium ethylate for saponification of the neutralized tol- uene extract was also recorded. Combined benzoic acid is calculated from the difference between total and fre6 benzoic acid. In order to make a direct comparison of these possible, equivalent amounts were us6d. The urine in each case was diluted to a definite volur.i6 and an aliquot used for each determination. Benzyl succinate was made the standard in the amounts of the compounds used. 1£;1.5, and 2.0 grams of this ester were used according to the comparative weight of the animal, and equivalent amounts of the other compounds cal- culated from these values. IV. Discussion As shown by these tables, the elimination of these compounds fed, varies greatly with the individual animal. As we are most in- terested in the comparison of the succinate with the other compounds its relation is the most important. In table IV and V we find it elii inated more slowly than the other compounds but its recovery was more complete. In table V, it was eliminated at the same rate as sodium benzoate, but its recovery was much more complete. Here it is also eliminated more rai^idly than the alcohol or acetate. Yet in tables VII and Ik , the elim- ination was very 3low, and not as complete a recovery as of the al- Q. cohol or acetate was obtained, although the recovery of these was very incomplete. In tables VIII and IX with feeding the succinate only, we find the elimination greater during the first eight hours in one case and greater during the last sixteen hours in the other. The greater elimination of the succinate in the first eight hours is also found in table XI. In table IV, X and XII, sodium benzoate was eli] inated most ra- pidly, but in table XII more of the succinate was recovered. Ben- zyl acetate was the most completely recovered of these compounds in tabl6 X, while it was the slowest to be eliminated in tabl6 XII. In the latter table there was also a slow elimination of the succi- nate but faster than that of the alcohol and more complete than the acetate or sodium benzoate. The low results in tables XI and XII may be due to a poor nu- tritive condition of the animal, later resulting in death. In tables IV, V and VI, are given the amounts of alkali requir- ed for saponification of the sample. This determination was omitted in the subsequent experiments, since it was practically constant af- ter feeding these compounds. In tables XI and XII the free benzoic acid determination was omitted since it also remained almost constant during the feeding of these derivatives. The amount of benzoic acid eliminated, wheth- er free or combined is of interest in this work, mor6 than the form of the benzoic acid. ■ . , ' V 9 V. General Conclusion Benzyl succinate is alowly But completely eliminated in the urine as hippuric or fre6 benzoic acid. VI. Summary I. An attempt was made to study the action of hog liver lipase upon benzyl succinate, but due to the insolubility of the ester, and the failure to obtain a good emulsion, no definite results were ob- tained. II. The reagents used in the determination of total benzoic acid when tested on benzyl succinate or on benzyl alcohol caused only slight oxidation to benzoic acid. III. Benzyl alcohol, acetate and succinate and sodium benzoate wer6 fed to rabbits and the rate and completeness of the elimination of the hippuric acid in the urine was studied and compared. IV. The tables indicate that benzyl succinate is hydrolyzed in the animal body more slowly than the liquid or soluble esters, yet the recovery as benzoic acid seems to be the most complete. V. There was no increase of saponifiable matter in the urine after feeding this ester. This indicates that that ester is not absorbed or retained as such, but in the form of its cleavage pro- ducts Effect of Table I. the procedure for hippuric acid 10. upon benzyl succinate. Benzyl succi- nate taken. Benzyl succi- nate equiva- lent to ben- zoic acid. Benzoic a- cid found. 3enzyl succi- nate oxidized to benzoic a- cid . g* mg. mg. 55 2.0000 1640.0 1074.0 6.5 1.0000 820.0 52.00 6.3 .6470 530.0 30.00 5.7 .5000 410.0 31.70 7.7 .2419 200.0 18.00 9.0 .2000 164.0 9.44 5.7 .1915 157.0 18.30 11.7 .1511 123.7 14.60 11.8 Table II. Effect of the procedure for hippuric acid upon benzyl alcohol. Benzyl alco- Benzyl alco- Benzoic Extra ben- Benzoic alee- hoi added to hoi equiva- acid zoic acid hbiaoxidized urin6 . lent to ben- found found to benzoic zoic acid. acid . 8 • mg. mg. mg. $ 0 > 0 36 • 6 . 0 0 36.6 — .800 903.7 54.0 17.4 1.9 .800 903.7 48.2 11.6 1.3 11 Table III. Recovery of compounds added to urine by methods used upon experimental urine. Experiment . BE1TZ0IG ACID Added as i ' Recovered. I f I. mg. Sodium benzoate 84.7 Benzyl succinate 81.9 Hippuric acid 34.1 mg. 88.0 97.8 70.3 Jo 103.9* 119.5* 206.0* Sodium benzoate 100.0 96.0 96.0 II. Benzyl succinate 82.0 76.8 93.7 Hippuric acid 34.1 66.7 195.5* Hippuric and benzoic acids and saponifiable matter are known to be present in the urine and corrections were not made for these amounts, hence the percentages. V - * * ' F : h u . 12. Table IV. Rabbit I. --male weight = 2.46 kg Daily diets 150 go. milk and 10 g. sucrose and 10 g. oats. Per- Dura- Benzyl Benzoic Acid I; Alkali Benzyl der- Benzyl iod. tion Der iva - To- F ree Com for sap- ivative fed. compound tive tal bined. onifica- calculated recover- used tion of as behzoic ed as ben toluene extract . acid. zoic acid I. hrs . 72 (24)* mg. IPS* 139.6 (46.5) mg. 16.0 (5.2) ms. cc. 123.6 12.8 (41.3) (4.3) mg. / 0 II. 24 Benzyl succi- nate 1000 634.4 31.6 602.8 8.8 819 71.8 III. 24 — 205.0 2.1 202.9 3.2 19.4 IV. 72 __ 224. 5.1 218.9 6.2 * • (24)* - ( 75) ( 1 . 7 ) ( 72 . 6 ) (2.1) _ V. 24 Benzyl alcohol 720.1 5.1 714.9 4.5 833.4 80.8 VI. 24 (737.8) 86.4 3.4 83.0 4.1 4.8 VII. 24 ~ 66 .4 3.4 63.4 4.9 2.4 VIII. 48 .. ' ' e 108.6 5.7^102.9 6.96 (24)* (54.3) (2.9) (51.4) (3. 5) IX. 24 2SS5&,**. a. 3.4 705.4 3.3 823.6 80.4 1012.6 X. 24 — 87.2 3.4 83.8 3.0 _ 4.94 XI. 24 . — _ 60.8 3.4 57.4 3.8 __ 4.6 XII. 48 (122 3.4 118.6 3.4 (24)* ( 61) (1.7) (59.3) (1.7) — — * Average per 24 hours. 13. Table V. Rabbit 2. male weight 2.60 kg. Daily diet : 150 cc. milk and 10 g. sucrose and 10 g. oats. Benzyl BENZOIC ACID alaka- 10 li for Benzyl deriva- Benayl canpoun* Per- iod Dura- tion deriva- tive used To- Free Combined tal saponifi- cation of toluene extract tive fed calcula- ted as benzoic acid recovered as ben - zoic acid hrs. mg. mg . mg • mg . cc . mg. P I 72 __ 218.6 5.1 215.5 11.08 _ _ (24) * ( 72.9 )( 1.7 )( 71.2) (3.7) II. 24 Benzyl acetate 1109.0 751.2 7.2 744.0 5.52 902 75.2 ; III. 24 156.8 16.8 120.0 4.8 7.0 IY. 24 l 61.0 15.6 47.4 4.7 V. 48 101.7 17.8 85.9 6.28 (24) * ( 50.9) (8.9) (42.0) 3.14 VI. 24 Benzyl succi- nate 1000 664. 5.1 658.9 4.19 819 74.9 VII. 24 152.7 5.1 147.6 5.0 12.4 VIII. 24 — 71.2 5.4 67.8 4.11 — 2.5 * Average per 24 hours. 14. Table VI. Rabbit 3 male weight 2.54 kg. Daily diet: 15Q cc. milk and 10 g . sucrose and 15 g. oats . Ben zyl B3UZ0IC ACID [ alaka- 10 li for aaponifi- Benz yL da?iva- tive fed Benzyl c ompound recovered Per- iod deriva - Dura-tive tion used m Tbtal Free Combined cation of toluene extract oakuliar- tod as bsnz>ic a as benzo- ic acid hrs mg. mg. mg . mg. cc . mg. / U I. 72 183.2 2uQ 163.2 10.88 _ __ (24)* _ (613 (6.7) (54.4) (3.63) . r _ II. 24 Bersyl succi- nate 2000 1375.2 39. 1337.2, 4.51 1639 80.3 III. 24 132.8 10.1 122.7 2.64 4.38 IV. 24 122.2 3.9 118.3 3.87 3.72 V. 72 152.6 67.8 84. % 5.96 (24)* _ (50P) (22 .6) (28.3 (1.99) VI. 24 Benzyl acetal e 2013.5 1236. 20.8 1215.2 2.24 1637. 7 72.3 VII. 24 __ 135.2 20.8 114.4 2.40 _ 5 J. 5 VIII. 24 '71. 5 6.9 64.6 2.24 __ . 1.60 IX. 48 109.0 15.6 93.4 6.0 (24)* (54.3 (7.8) (46.7) (3.0) X. 24 Benz yl alcchoL 1828.0 1512. 8 2.8 15 ia 2.56 2065 70.5 XI. 24 134.7 5.2 129.5 2.0 3.88 XII. 24 78.1 3.5 74.6 2.8 _ 1.14 XIII. 48 92.8 7.8 85.0 5.36 — — Table VI. (cont . ) (24)* _ (46.4) (3.9) (42.5) (1.68) , - - XIV. 24 Sodium benzoate 1933 1376. 8.8 1367.2 3.04 1637.1 81.2 XV. 24 62.5 5.2 57.3 2.67 _ .99 XVI. 24 73.2 5.2 68.0 2.40 LS4 XVII. 48 93.6 13.2 8014 3.8 (24)* __ (46.8) (6.6) (40.2) (1.9) — — * Average p6r 24 hours. 16 Table VII. Rabit 4 male weight: 2.06 kg. Daily diet : 150 cc . milk and 10 g. sucrose and 15 g. oats. Per- iod Dura- tion Wt. Benzyl deriv- ative used Benzoic To- Dree tal Acid Com- bined B al. Ben. 10 der. for sap* fed onifi. cal. of tol. ben- extract zoic Benzyl c omp . recov- ered as benzoic acid. hrs . kg. mg. mg. mg. mg. c c . mg . fo I 96 2.04 -- 536.8 238.5 298.3 5.95 -- ( £4)* -- -- ( 134. 2)(. 59.6) (74.6) (1.49) -- II. £4 2.08 Benzjfc. sue . 1500 525.6 1.7 323.9 2.11 1228.5 15.6 III. 24 2.08 -- 685.6 5.2 680.4 2.67 45.0 IV. 24 ^ • _L — 122. 5.2 116.8 2.67 --- V. 48 2.10 -- 301.6 10.4 291.2 4.4 -- (24)* — — (150.8) ( 5.2 ) ( 145.6) (2.2) -- VI. 24 2.10 Benzyl acetat 1511.7 980.9 17.6 e 963.3 2.24 1219.5 68.2 VII. 24 2.13 -- 73.6 7.2 66.4 2.24 -- VIII. 24 2.13 -- 98.6 5.2 93.4 2.4 -- IX. 48 2.18 -- 192.3 10.4 181.9 3.36 -- (24)* — -- (96.2) (5.2) (91.0) (1.68) -- X. 24 2.17 Benzyl 1005.3 10.4 alcohol. 1087.3 994.9 2.1 1 228.3 74.1 XI. 24 2.16 -- 93.7 5.2 88.5 2.4 -- XII. 24 2.19 -- 73.2 5.2 68.0 2.11 -- XIII . 48 2.25 -- 145.6 21.2 124.4 3.16 -- (24)* -- — (72.8) (10.6) (62.3 (1.58) -- * Average per 24 hours , . . «■ - •> ,j * 4 ' t 1 17. Cable VIII Rabbit 6 male weight : 2.12 kg. ! Daily diet : 150 cc. milk and 10 s:. sucrose and 15 sr oats Per- iod Dura- tion - Benzyl de- Benzoic Acid rivative used To- Tree Com- tal bined Benzyl de- rivative used, cal- culated as benzoic acii Benzyl de rivative recovered as benzoic acid. hrs mg. mg. mg. mg. mg. $ I. 24 85.7 15.9 69.7 — -- II. 8 benzyl sue cinate 1500 - 315.0 — 1228.2 18.68 III. * 16 732.0 -- 52.80 Rabbit 7 male Cable 12 weight: 2 .6 kg. \ Daily diet : 150 cc. milk and 10 g. sucrose and -L • • 0 ctlj S • I. 24 -- 124.2 — -- . II. 8 benzyl suc- cinate 2000 995.4 23.4 972.0 1637.6 53.5 III. 16 -- 336.7 3.9 332.8 — 13.0 IV. 24 -- 212.3 3.9 208.4 — 5.38 V. * 24 — 94.2 3.9 90.3 — — * Died 18. m able X. Rabbit 8 male weight: 2 .06 kg. Daily diet : 150 cc. milk and 10 g. sucrose and 15 g. oats Per- iod Dura- tion Benzyl de- rivative used Benzoic Total Free Acid Combined Benzyl deri- vative used calculated as benzoic Benzyl com- pound re- covered as benzoic acid hrs. mg. mg. mg. mg. mg. fo I 24 — 95.2 5.9 89.3 " -- -- II 8 Benzyl sue . 1500.0 156. 3.9 152.1 1228.2 4.9 III. 16 — 497.8 5.9 491.9 -- 32.8 IV. 24 -- 417.3 5.9 411.4 -- 25.75 V. 24 -- 175.7 5.9 169.8 — 6.6 VI. 8 Sodium benzoate 1449.7 1024.8 9.9 1014.9 1228.2 75.7 VII. 16 -- 205.0 11.7 193.3 -- 8.94 VIII. 24 -- 105.4 11.7 93.7 — .83 IX. 8 Benzyl alcohol 1087.3 863.8 5.9 857.4 1228.2 62.60 X. 16 — 285.6 3.9 281.7 -- 15.50 : XI. 24 — 117.1 5.9 111.2 — 1.80 XII. 8 Benzyl acetate 1501.1 863.8 5.9 857.9 1228.2 62 • 60 XIII. 16 -- 448.5 -- -- -- 28.77 XIV. 24 214.8 9.74 Rabbit Daily 9 diet : male 150 cc. milk Table XI. and 10 g. sucrose weight: 2. and 15 g. oats 19. 61 kg. Per- iod Dura- tion Benzyl de- rivative used Benzoic Acid To;bal Benzyl de- rivative used cal- culated as benzoic ac. Benzyl compound recovered as benzoic acid hr s. mg. mg. mg. I. 24 — 109.1 — — II. 8 Benzyl suc- cinate 2000 923.1 1637.6 49.7 III. 16 -- 338.9 — 14.04 IV. 24 -- 194.7 -- 5.25 V. 24 -- -- -- -- VI. 8 Sodium benzoate 1932.9 763.5 1637.6 39.9 VII. 16 -- 219.6 -- 6.76 VIII. 24 -- 131.3 -- 1.35 IX. 24 — -- -- — V • 8 Benzyl alcohol 1449.7 728.4 1637.6 37.8 XI. 16 543.4 — 26.57 XII. 24 — 346.9 -- 14.52 XIII. 24 -- — -- — XIV. * 8 * Benzyl acetate 2012.3 339.2 1637.6 14.07 * Died • V 20. Table XII. Rabbit 10 Female v/ei ght : 1 • 5 • Daily diet : 150 cc . milk and 10 g. sucrose and 10 g. oats . Period Dura- tion Benzyl de- rivative used Benzoic acid Benzyl de- rivative used cal- culated as benzoic a. Benzyl com- pound recov- ered as ben- zoic acid. hrs. mg. mg. mg. /o I. 24 -- 139.1 -- -- II. 8 Benzyl sue . 1000 454.8 818.8 38.6 III. 16 -- 358.7 -- 26.8 IV. 24 -- 138 . 7 — -- V. 24 -- -- -- — VI. 8 Sodium benzoate 966.5 616.6 818.8 58.4 VII. 16 -- 116.7 -- -- VIII. 24 -- 65.5 -- -- IX. 8 Benzyl alcohol 724.9 354.6 818.8 35.3 X. 16 -- 416.2 — 42.19 XI. 24 — 65.5 -- -- XII. 8 Benzyl acetate 1006.7 381.5 818.8 38.7 XIII. 16 -- 185.0 -- 14.6 XIV. 24 119.5 6.6 . . * 21 . Tables XIII Comparison of the elimination of benzyl succinate, benzyl alcohol, benzyl acetate and sodium benzoate. Rate of el ini nation Completeness of elimination Rabbit no . 1 2 3 4 8 o mt 10 1 2 3 4 8 9 10 Benzyl cinate sue- 3 2 2 5 4 1 3 1 1 1 3 4 2 2 Benzyl cohol al- 1 4 1 o 3 4 3 4 1 2 1 1 Benzyl tate ace- 2 1 3 2 3 4 2 2 2 3 2 1 4 3 Sodium zoate ben- 1 1 2 1 2 3 3 4 0 " & 1 . . 22 VII. Bibliography. (1) Filippi E. — Arch, di Farm. 1914, XVIII, 178-211 (2) Macht D.I.--J. of Pharm. and Exp. Eher. 1918 XI, 263-7. (3) Macht D.I. and llelson D.X. — Proc. 3oc. Exp. Biol. led., 1918, XVI. 25-6 (4) Macht D.I. and Satani Y.--J. Pharm. Exp. Eher . Proc., 1920, XV. , 244 (5) Macht D.I., Satani Y. and Schwartz E.0.--J. Urol., 1921, IV. 355-61 (6) Macht D.I.--J. Pharm. and Exp. Iher. 1919, XIII, 509 (7) Sollnan ?. — J. Pharm. a. id Exp. Ther . 1919 XIII 355-60 (8) Voegtlin C. and Livingstone A.E.--J. Pharm. and Exp. Eher. Proc. 1919, XIII 515-4 (9) Mason E.C. and Pieck C.E.--J. Lab. and Clin. Med., 1920, VI. 62-77 (10) Heller E.A. and Steinfield £. — H.Y.Med.J., 1920, CXI I, 160-1 (11) Hielson C. and Higgins— J. A.— J. Lab. and Clin. Med., 1921, VI. 388-92 (12) Hielson C. and Higgins J.A.--J. Lab. and Clin. .led., 19-.1, VII. 69-82 (13) Macht D.I. --Proc. Soc. Exp. 3iol. Med. 1921, XVIII, 177-9 (14) Volwiler E.H. and Vliet E.B. --J.A. C . 3. 1921, .^IIT , 16 1 (15) Shonle H.A. and Row P.G. — J.A.C.S. 1921, XLIII, 361-5 ( 16 ) Kingsbury F.B. and Swanson — J.B.C. 1921, .al .III, 1 - a 1 (17) Raiziss G.Y/. and Dubin H. — J.B.C. 1915, XVI, 125