Mephenytoin N-demethylation

B6 Artemisinin, bupropion, cyclophosphamide, S-mephobarbital, S-mephenytoin (N-demethylation to nirvanol), propofol, selegiline, sertraline Phenobarbital, cyclophosphamide. S -Mephenytoin... 

CYP2B6 is present at low level (< 1 %) in the liver. It catalyzes bupropion hydroxylation, S-mephenytoin N-demethylation, is involved in the metabolism of cyclophosphamide, ifosfamide, mianserin and propofol. CYP2B6 6 has been associated with reduced bupropion clearance in vitro (Hesse 2004), but not in vivo whereas a moderate clearance increase was observed with CYP2B6 4 (Kirchheiner 2003). Bupropion (150 mg dose) has been proposed for phenotyping, but it is recommended to adjust dose based on subject weight (Faucette 2000). 

Mephenytoin is N-demethylated to 5,5-phenyl-ethylhydantoin and it is this active metabolite probably mainly accounts for the therapeutic benefit and toxicity. Serious toxicity is common, and mephenytoin is generally used only in patients who fail to respond to or do not tolerate safer agents. Mephenytoin is no longer available in the US or the UK. 

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). 

R) -mephenytoin is slowly N-demethylated to nirvanol, an active metabolite. "Poor metabolizers," however, appear to totally lack the stereospecific (S)-mephenytoin hydroxylase activity, so both... 

Imipramine is metabolized mainly by N-demethylation and 2-hydroxylation in man. The N-demethylation pathway has been shown, in vitro, to be mediated by CYP2C19 at low imipramine concentrations (91). In vivo the partial clearance of imipramine, via N-demethylation, was shown to be significantly reduced in PMs of (S)-mephenytoin (94). In addition, a much larger study showed that the S/R ratio for mephenytoin correlated with the N-demethylation of imipramine (95). 

Chiba K, Saitoh A, Koyama E, et al. The role of (S)-mephenytoin 4 -hydroxylase in imipramine metabolism by human bver microsomes a two-enzyme analysis of N-demethylation and 2-hydroxylation. Br J Cbn Pharmacol 1994 37 237-242. 

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. 

Skjelbo E, Gram LF, Brosen K. The N-demethylation of imipramine correlates with the oxidation of (5)-mephenytoin (S/R ratio). A population study. Br J Clin Pharmacol 1993 35 331-334. 

Ko JW, Desta Z, Flockhart DA. Human N-demethylation of (S)-mephenytoin by cytochrome P450s 2C9 and 2B6. Drug Metah Dispos 1998 26 775-778. 

Koyama, E. Chiba, K Tani, M. Ishi-zaki, T. Reappraisal of human CYP isoforms involved in imipramine N-demethylation and 2-hydroxylation a study using microsomes obtained from putative extensive and poor metaholi-zers of S-mephenytoin and eleven recombinant human CYPs,... 

Diazepam is primarily metabolized by hepatic cytochrome enzyme responsible for S-mephenytoin hydrox-ylation, with very little unchanged drug eliminated in the urine [1,2]. Hepatic N-demethylation results in the formation of the active metahohte desmethyldiazepam. This metabolite is hydroxylated to form oxazepam. Another minor active metabohte is temazepam. The half-life ty )of diazepam ranges from approximately 24 hours to more than 48 hours. With chronic dosing, steady-state concentrations of diazepam are achieved between 5 days and 2 weeks. The half-life is prolonged in the elderly and in patients with cirrhosis or hepatitis. 

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