S-Mephenytoin

Cytochrome P450 2C19, also termed S-mephenytoin hydroxylase, is a mixed-function oxidase localized in the endoplasmic reticulum which is responsible for the biotransformation of S-mephenytoin, some barbiturates, almost all proton pump inhibitors such as omeprazole, diazepam and others. 

CYP2C19 is another example of the existence of both cross-ethnic and inter-individual variations in drug metabolism. This enzyme is involved in the metabolism of many psychotropics such as diazepam and tertiary tricyclic antidepressants, as well as one of the selective serotonin re-uptake inhibitors (SSRIs), citalopram. Using S-mephenytoin as the probe, previous studies showed that up to 20% of East Asians (Chinese, Japanese, and Koreans) are PMs, when only 3-5%... 

Xie, H. G., Stein, C. M. et al. (1999). Allelic, genotypic and phenotypic distributions of S-mephenytoin 4 -hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics, 9(5), 539-49. 

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

Inoue, K. et al. (1997). Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4 -hydroxylation activities in livers of Japanese and Caucasian populations. Pharmacogenetics, 7, 103-13. 

Roh, H. K. etal. (1996). Debrisoquine and S-mephenytoin hydroxylation phenotypes and genotypes in a Korean population. Pharmacogenetics, 6, 441-7. 

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. 

Andersson T, Regardh CG, Dahl-Puustinen ML, Bertilsson L. Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators. Ther Drug Monit 1990 12[4] 415-416. 

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. 

FIGURE 4.10 Structures of the CYP2B6 substrates, 7-ethoxy-4-trifluoromethylcoumarin and (S)-mephenytoin, and their metabolites. 

FIGURE 4.12 Structures of the CYP2C19 substrates, (S)-mephenytoin and omeprazole, and their metabolites. 

Ibeanu, G. C., BlaisdeU, J., Ghanayem, B. 1., et al. (1998) An additional defective allele, CYP2C19 5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics. 8, 129-135. 

Values were back calculated from actual in vivo DDI data for fluconazole and S-warfarin (fee, CYP2C9 = 0.91), fluvoxamine and theophylline (fcL,CYPiA2 = 0.8), fluvoxamine and S-mephenytoin (fcL,CYP2C9 = 1). ketoconazole and midazolam fcL,CYP3A,hepatic = 0.93), and quinidine and desipramine (fcL,CYP2D6 = 0.9). 

B6 Artemisinin, bupropion, cyclophosphamide, efavirenz, ifosfamide, ketamine, S-mephobarbital, S-mephenytoin (/V-demethylation to nirvanol), methadone, nevirapine, propofol, selegiline, sertraline, ticlopidine Phenobarbital, cyclophosphamide Ticlopidine, clopidogrel... 

C19 Diazepam, S-mephenytoin, naproxen, nirvanol, omeprazole, propranolol Barbiturates, rifampin /3-benzylnirvanol, N3- benzylphenobarbital, fluconazole... 

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). 

G. Ibeanu, J. Blaisdell, B.I. Ghanayem, C. Beyeler, S. Benhamou, C. Bouchardy, G.R. Wilkinson, P. Dayer, A.K. Daly, J.A. Goldstein, An Additional Defective Allele, CYP2C19 5, Contributes to the S -Mephenytoin Poor Metabolizer Phenotype in Caucasians , Pharmacogenetics, 8,129-135 (1998). 

Chiba et al. [163] studied the oxidative metabolism of omeprazole in 14 human liver microsomes in relation to the 4 -hydroxylation capacity of S-mephenytoin. The formation of 5-hydroxyomeprazole and omeprazole sulfone from omeprazole exhibited a biphasic kinetic behavior, indicating that at least two distinct enzymes are involved in either of the metabolic pathways of omeprazole. These findings suggest that S-mephenytoin 4 -hydroxylase is an enzyme primarily responsible for the 5-hydroxylation of omeprazole and further metabolism of omeprazole sulfone, but not for the sulfoxidation of omeprazole in human liver microsomes. 

In normal "extensive metabolizers," (S)-mephenytoin is extensively hydroxylated by CYP2C19 at the 4 position of the phenyl ring before its glucuronidation and rapid excretion in the urine, whereas... 

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