Mephenytoin, inhibition

Zhao and Lou [164] studied the metabolism of omeprazole to its two major metabolites, hydroxyomeprazole and omeprazole sulfone, in rat liver microsomes by a reversed-phase HPLC assay. The formation of metabolites of omeprazole depended on incubation time, substrate concentration, microsomal protein concentration, and was found to be optimal at pH 7.4. The Pmax and Km of omeprazole hydroxylation in the rat liver microsomal preparation were 2033 nmol /(min mg protein), and 46.8 ymol/l, respectively. The effects of seven drugs on omeprazole metabolism were tested. Mephenytoin, five benzodiazepines and pava-verine caused inhibition of omeprazole metabolism. 

Schellens JH, van der Wart JH, Brugman M, et al. Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a cocktail study design. J Pharmacol Exp Ther 1989 249 638-645. 

CYP2C18/ 2C19 Liver CYP2C19 2 CYP2C19 3 (S)-mephenytoin 4 -hydroxylation (preferred1) Ticlopidine (acceptable1, also inhibits CYP2D6) Ketoconazole Rifampicine Carbamazepine < 5%... 

B6 S-Mephenytoin (N-desmethyl metabolite) Bupropion Sertraline (but also inhibits 2D6)... 

C19 2D6 Mephenytoin (4-hydroxy metabolite), Omeprazole Bufuralol, Dextromethorphan Metoprolol, Debrisquine, Codeine Tranylcypromine Quinidine Ticlopidine (but also inhibits 2D6), Nootkatone (but also inhibits 2A6)... 

Laine K, Tybring G, Bertilsson L. No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin Pharmacol Ther 2000 68 151-9. 

The mephenytoin metabolic pathway is utilized by commonly used drugs, such as mephobarbital, hexobarbital, diazepam, imipramine and omepra-zol, but only 3-5% of Caucasians and 8% of Blacks are poor metabolizers of mephenytoin, compared to 15-20% of Chinese and Japanese populations (Kupfer et al., 1988). This enzyme s activity is inhibited by floconazole and fluoxetine and induced by drugs such as barbiturates and nicotine (smoking). 

FIGURE 16.5 Celecoxib inhibition of CYP2C19-catalyzed (5)-mephenytoin 4 -hydroxylation in human liver microsomes Y ax = 0.40 0.02 nmol/min/mg, = 13.8 1.9 xM, Ki = 3.2 0.4 xM, RSS = 0.002, and = 0.981, respectively. All kinetic values were determined by multiple nonlinear regression (3-dimension) using the velocity equation of competitive inhibition in Table 16.3. 

To assess selectivity in the inducing and inhibiting effects of environmental factors (for example, dmg treatment) on the activity of the different P-450 enzymes. In one of such smdies, nifedipine, sparteine, mephenytoin and antipyrine were administered simultaneously to 15 healthy subjects, including four poor metabohzers of sparteine and four poor metabolizers of mephenytoin [6], They received the cocktail on three different occasions without pretreatment, after pentobarbital pretreatment and together with cimetidine. Concentrations of nifedipine, its pyridine metabolite, and of sparteine and its dehydro metabolite were measured in the plasma nifedipine metabohtes, sparteine, dehydrosparteine, 4-hydroxymephenytoin, antipyrine and its three major metabohtes were all measured in urine. The kinetic parameters obtained clearly indicated that nifedipine metabolism is very sensitive to pentobarbital induction (Fig. 4), whereas antipyrine metabolism is sensitive only to a moderate degree and sparteine metabolism is unaffected. Cimetidine inhibited the metabohc clearance of all three compounds to a similar extent and also inhibited renal clearance of sparteine, most likely at the level of tubular secretion. Urinary excretion of 4-... 

Kava does not appear to affect the metabolism of debrisoquine and mephenytoin. Kava may inhibit the metabolism of chlorzoxazone but not all studies have found this effect. 

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