Mephenytoin, polymorphic metabolism

Jacqz E, Hall SD, Branch RA, et al. Polymorphic metabolism of mephenytoin in man pharmacokinetic interaction with a co-regulated substrate, mephobarbital. Clin Pharmacol Ther 1986 39 646 653. 

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. 

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). 

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. 

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. 

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. 

Ibeanu GC, Blaisdell J, Ferguson RJ, et al. A novel transversion in intron5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolism of the anticonvulsant drug S-mephenytoin. J Pharmacol Exp Ther 1999 290 635-640. 

Brosen K, Skjelbo E, Flachs H. Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark. Br J Clin Pharmacol 1993 36 105-108. 

Figure 4 Polymorphic drug oxidations by cytochrome P450. A, substrates subject to debrisoquine/sparteine polymorphism. R(+)-bufuralol is I -hydroxyl-ated by P450-IID6 the S(—)-enantiomer undergoes hydroxylation at the 2- and 4-positions debrisoquine is hydroxylated at the prochiral C4-atom to S(+)-hydroxy-debrisoquine sparteine metabolism by P450-IID6 consists of N-oxidation. B, substrates subject to hydantoin polymorphism (4 -hydroxylation). Extensive metabolizers convert S(+)-mephenytoin and -nirvanol to the 4 -hydroxy derivative (indicated by the arrow). Similarly, EMs metabolize the prochiral drug phenytoin to R(+)-4 -hydroxyphenytoin. = chiral center.

A major source of intersubject variability for stereoisomers is polymorphism in drug biotransformation. " Extensive metabolizers of metoprolol display higher clearances of both stereoisomers than poor metabolizers, but the magnitude of the differences between stereoisomers is not the same within each population. Extensive metabolizers of metoprolol require lower total (R and 5) plasma concentration of metoprolol for the same degree of beta blockade. In addition, R-mephenytoin shows similar oral metabolic clearance in extensive and poor metabolizers, whereas 5-mepheny-toin, which undergoes 4-hydroxylation, has markedly higher clearances in extensive metabolizers. ... 

CYP2C19 (mephenytoin hydroxylase) is also associated with marked interethnic differences. This enzyme metabolizes diazepam and several antidepressants (Pi and Gray 1998). Between 2% and 10% of whites have little or no activity of this enzyme, whereas 15%-25% of Asians maybe PMs (Horaietal. 1989 Kupfer and Preisig 1984 Pi and Gray 1998). In addition, there is also evidence of polymorphism among EMs, with some Asian EMs having a form of the enzyme with less activity than that of the form commonly found in Caucasian EMs (Sjoqvist et al. 1997). 

Genetic polymorphisms in CYP450 isoenzymes are common. Among whites, 5-10% of the population carries a mutation of CYP450 2D6, causing them to be slow metabolizers of debriso-quine, mephenytoin, quinidine, metoprolol and dextromethorphan standard doses are more likely to be associated with adverse events as a consequence, especially when a second substrate drag is interacting. 

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