Oxidative metabolism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation

RG Knodell, RK Dubey, GR Wilkinson and FP Guengerich

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.

The major route of hexobarbital metabolism in humans involves hydroxylation at the 3'-position followed by oxidation to a 3'-keto metabolite. Studies were performed to characterize the form of cytochrome P-450 responsible for the initial oxidation. In vitro studies indicated that P-450MP purified from human livers, involved in the 4-hydroxylation of S-mephenytoin, efficiently catalyzed the 3'- hydroxylation of hexobarbital; moreover, polyclonal antibodies raised to this enzyme extensively inhibited such activity in human liver microsomes. S-Mephenytoin 4- and hexobarbital 3'-hydroxylase activities in microsomes from different livers were significantly correlated, and both activities were essentially absent in fetal liver preparations. Hexobarbital was also found to inhibit S-mephenytoin 4-hydroxylation and vice versa, with Ki values similar to the Km values for the measured pathways. These data suggested that in vivo metabolism of hexobarbital would be determined by the same genetic factor(s) responsible for polymorphic 4-hydroxylation of S-mephenytoin. This prediction was confirmed by the finding that, after oral administration of a single dose of hexobarbital (300 mg), the 24-hr urinary excretion of 3'-hydroxy- and 3'-ketohexobarbital in a "poor-metabolizer" was only one third of that in a subject of the "extensive-metabolizer" phenotype. Also, the plasma level of metabolites at 6 hr after administration was reduced, and that of unchanged drug was increased in the poor metabolizer. Finally, a markedly enhanced sedative effect was associated with the impaired metabolism. Accordingly, several lines of in vitro evidence indicate that hexobarbital 3'-hydroxylation is catalyzed by P-450MP.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 245, Issue 3, pp. 845-849, 06/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				J. A. Williams, T. Andersson, T. B. Andersson, R. Blanchard, M. O. Behm, N. Cohen, T. Edeki, M. Franc, K. M. Hillgren, K. J. Johnson, et al. PhRMA White Paper on ADME Pharmacogenomics J. Clin. Pharmacol., July 1, 2008; 48(7): 849 - 889. [Abstract] [Full Text] [PDF]

				S. J. Gardiner and E. J. Begg Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice Pharmacol. Rev., September 1, 2006; 58(3): 521 - 590. [Abstract] [Full Text] [PDF]

				K. Kim, J. A. Johnson, and H. Derendorf Differences in Drug Pharmacokinetics Between East Asians and Caucasians and the Role of Genetic Polymorphisms J. Clin. Pharmacol., October 1, 2004; 44(10): 1083 - 1105. [Abstract] [Full Text] [PDF]

				D. Kim, E. Kim, S. Han, J. Roh, T. Jeong, and J. Park Inhibitory effects of H2-receptor antagonists on cytochrome P450 in male ICR mice Human and Experimental Toxicology, August 1, 1995; 14(8): 623 - 629. [Abstract] [PDF]

				Y.W. F. Lam and M. V. Marshall Genetically Determined Polymorphisms in Drug Metabolism Journal of Pharmacy Practice, January 1, 1992; 5(6): 317 - 336. [Abstract] [PDF]