RT Journal Article SR Electronic T1 THE ROLE OF DIHYDROPYRIMIDINASE IN THE METABOLISM OF SOME HYDANTOIN AND SUCCINIMIDE DRUGS JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 103 OP 112 VO 2 IS 2 A1 KENNETH H. DUDLEY A1 THOMAS C. BUTLER A1 DANIEL L. BIUS YR 1974 UL http://dmd.aspetjournals.org/content/2/2/103.abstract AB An enzyme that converts 5-phenylhydantoin to 2-phenylhydantoic acid was found in the liver of the rat, mouse, guinea pig, rabbit, and dog. The enzyme was also found in the kidney of all these species except the mouse but in none of the other tissues investigated. The enzymatic activity was present in the 100,000g supernatant fractions of liver and kidney homogenates. Only the R(-)-enantiomer of 5-phenylhydantoin is a substrate of the rat liver enzyme. Metabolism of the S(+)-enantiomer of 5-phenylhydantoin is consequent to racemization promoted by general base catalysis. Reversibility of the conversion of 5-phenylhydantoin to 2-phenylhydantoic acid by the rat liver enzyme is demonstrable. Only R(-)-2-phenylhydantoic acid is enzymatically converted to 5-phenylhydantoin. α-Phenylsuccinimide is also metabolized by the rat liver enzyme to 2-phenylsuccinamic acid. Alkylation of the imide nitrogen or disubstitution of the carbon juxtapositional to the imide carbonyl renders a hydantoin or succinimide insusceptible to this enzymatic hydrolytic cleavage. Present evidence indicates that the enzyme that hydrolyzes the hydantoin and succinimide drugs is identical to dihydropyrimidinase (4,5-dihydropyrimidine amidohydrolase, EC 3.5.2.2), the natural substrates of which are dihydrouracil and dihydrothymine. Copyright © 1974 by The American Society for Pharmacology and Experimental Therapeutics