XI. PHARMACOLOGY 53 



t'oiivertod to p-aminohippuric acid and excretod iii this form in the urine. 

 ConversicMi of PABA occurnHl in the li\er, noimally being ra])id, hut was 

 depressed in primaiy ii\'er thsease.'" Apparently the p-anunohipi)urate is 

 the main excretory form, l)ul there is still another. According to Tabor 

 and coworkers," man excreted wvy little PABA in eithei- the free; or acetj'- 

 lat(>d foiins, excretion occurring mainly as a conjugation ))i(Kluct with 

 glycine or glucuronic acid. Zarafonetis and Chandler'- also noted the re- 

 ducing substance, glucuronic acid, in urine of i)atients receiving large doses 

 of PABA. Dogs w(Me found to excrete p-aminohippuric acid when PABA 

 administration was prolonged.' 



Acetylation of PABA in various species of cold-blooded animals is like- 

 wise variable. Chen and associates''' found that the spadefoot toad and the 

 nebulous toad were able to acetylate PABA, whereas acetylation did not 

 oceiu" in the leopard frog or the turtle. 



Renal clearance studies have shown that excretion of PABA occurs 

 partly through secretion by the renal tubules as well as glomerular filtra- 

 tion.^*- '^ Secretion may be blocked by o-iodohippurate. 



Excretion is accomplished by routes other than the urinary tract. In 

 fact, Denko et aZ.'^ have found that fecal excretion is greater than urinary, 

 but this is probably owing to synthesis of PABA by intestinal flora. Johnson 

 ct al." noted a concentration of 0.24 7 per 100 ml. in the sweat of four 

 male humans. 



Studies on the entire animal have shown that mice metabolize PABA 

 rapidly." Xo significant amount of the substance can be detected after 8 

 hours. It appears to penetrate freely into the cells of liver, lung, and kidney, 

 l)ut only slowly into muscle, brain, and erythrocytes. N^^ studies by Lustig 

 c( al}^ likewise have revealed no measurable amount of PABA accumulating 

 in organs and tissues of injected mice. 



B. TOXICITY 

 Gibbs and Hare'* in 1889 concluded that PABA was without effect on 

 the animal organism. Doses of oOO mg. to 2 g. in dogs weighing 5 to 7 kg. 



10 W. P. Deiss and P. P. Colien, J. Clin. Invest. 29, 1014 (1950). 



" C. W. Tahor, .M. V. Freeman, J. Baily, and P. K. Smith, J. Pharmacol. Expil. 

 Therap. 102, 98 (1951). 



" C. J. D. Zarafonetis and J. P. Chandler, /. Lab. Clin. Med. 37, 425 (1951). 



>3 R. B. Failey, Jr., R. C. Anderson, F. G. Henderson, and K. K. Chen, ./. Phar- 

 macol Expd. Therap. 78, 366 (1943). 



'^ F. Lundquist, Ada. Pharmacol. Toxicol. 1, 307 (1945). 



•5 P. Terp, Acta Pharmacol. Toxicol. 7, 259 (1951). 



•« C. W. Denko, W. E. Grundy, J. W. Porter, G. H. Berryman, T. E. Friedemann, and 

 J. B. Youmans, Arch. Biochem. 10, 33 (1946). 



'^ B.C. Johnson, H.H. Mitchell, and T.S. \\-Am\\Um. .f . Biol. Che m. 161, 357 (1945). 



" B. Lustig. A. R. Goldfarl), and B. Gerstl. Arch. Biochem. 5, 59 (1944). 



19 W. Gibbs and H. A. Hare, Am. Chem. J. 11, 435 (1889). 



