Mephenytoin, polymorphic

Adedoyin A, Prakash C, O Shea D, et al. Stereoselective disposition of hexobarbital and its metabolites relationship to the S-mephenytoin polymorphism in Caucasian and Chinese subjects. Pharmacogenetics 1994 4 27-38. 

Daniel, H. I. Edeki, T. I. (1996). Genetic polymorphism of S-mephenytoin 4 -hydroxylation. Psychopharmacol. Bull, 32, 219-30. 

Bertilsson, L., Lou, Y. Q., Du, Y. L. et al. (1992). Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin. Pharmacol. Ther., 51, 338-97. 

Nakamura, K., Goto, F., Ray, W. A. etal. (1985). Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin. Pharmacol. Ther., 10,402-8. 

Xie HG, Kim RB, Stein CM, Wilkinson GR, Wood AJJ. Genetic polymorphism of (S)-mephenytoin 4 -hydroxylation in populations of African descent. Br J Clin Pharmacol 1999 48 402-408. 

Wedlund, P.J., Aslanian, W.S., McAllister, C.B., Wilkinson, G.R. and Branch, R.A. (1984) Mephenytoin hydroxylation deficiency in Caucasians frequency of a new oxidative drug metabolism polymorphism. Clinical Pharmacology and Therapeutics, 36 (6), 773-780. 

Relling, M.V., Evans, W.E., Fonne-Pfister, R., et al. (1989) Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes. Cancer Res. 49, 68-71. 

P. (1986) The molecular mechanisms of two common polymorphisms of drug oxidation—evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation. Xenobiotica 16, 449-464. 

CYP2C18 has been examined as a candidate for the (S)-mephenytoin 4 -hydroxylase polymorphism. Romkes et al. (1991) demonstrated that cDNA-expressed CYP2C18 4 -hydroxylated (5)-mephenytoin at a rate above background. However, CYP2C19 has recently been established as the protein responsible for the (5)-mephenytoin 4 -hydroxylase polymorphism (Wrighton et al., 1993 Goldstein et al., 1994). Population studies have demonstrated that 3-5% of Caucasians and about 20% of Asians are poor metabolizers of (5)-mephenytoin (Kalow, 1986). The molecular basis for this polymorphism has recently been established (de Morals et al., 1994). 

As with the hydroxylation of bufuralol, the hydroxylation is stereo-selective. Thus, only S-mephenytoin undergoes aromatic 4-hydroxy lation, and only this route is affected by the polymorphism. The R isomer undergoes N-demethylation. Poor metabolizers may suffer an exaggerated central response when given therapeutic doses (Fig. 5.29). 

A second well-studied genetic drug polymorphism involves the stereoselective aromatic (4)-hydroxylation of the anticonvulsant mephenytoin, catalyzed by CYP2C19. This polymorphism, which is also inherited as an autosomal recessive trait, occurs in 3-5% of Caucasians and 18-23% of Japanese populations. It is genetically independent of the debrisoquin-sparteine polymorphism. 

De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 1994 46 594-598. 

Kupfer A, Preisig R. Pharmacogenetics of mephenytoin a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 1984 26 753 759. 

Wedlund PJ, Aslanian WS, McAllister CB. Mephenytoin hydroxylation deficiency in Caucasians frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984 36 773-780. 

Wilkinson GR, Guengerich FP, Branch RA. Genetic polymorphism od S-mephenytoin hydroxylation. In Kalow W, ed. Pharmacogenetics of Drug Metabolism. New York Pergamon Press Inc., 1992 657-685. 

Andersson T, Regardh CG, Lou YC, Zhang Y, Dahl ML, Bertilsson L. Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects. Pharmacogenetics 1992 2 25-31. 

Ward SA, Helby NA, Skjelbo E. The activation of the biguanide antimalarial proguanil co-segragates with the mephenytoin oxidation polymorphism—a panel study. Br J Clin Pharmacol 1991 31 689-692. 

Sindrup SH, Brosen K, Hansen MG, Aaes-Jorgensen T, Overo KF, Gram LF. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 1993 15 11-17. 

Skjelbo E, Brosen K, Hallas J, et al. The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 1991 49 18-23. 

Alvan G, Bechtel B, Iselius L, et al. Hydroxylation polymorphism of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990 39 533-537. 

Goldstein JA, Blaisdell J. Genetic tests which identify the principal defects in CYP2C19 responsible for the polymorphism in mephenytoin metabolism. In Johnson EF, Waterman MR, eds. Cytochrome P450, Part B Methods in Enzy-mology. San Diego, CA Academic Press, 1996 272 210-218. 

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