Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbitone hydroxylation assessed in a phenotyped panel of healthy subjects.

Abstract

1 In a phenotyped panel of healthy subjects correlations were studied between the oxidation of mephenytoin, phenytoin, methylphenytoin and phenobarbitone, with respect to the formation of their 4-hydroxy metabolites (OH-). 2 On different occasions phenotyped extensive metabolizers (EM; n = 16) and poor metabolizers (PM; n = 4) of mephenytoin received phenytoin (100 mg), methylphenytoin (100 mg) and phenobarbitone (50 mg) and urine was collected up to 24 h. The excreted 4-hydroxy metabolites of all compounds were measured by h.p.l.c. 3 Urinary recovery of OH-phenytoin was 31.0 ± 11.7%, of OH-methylphenytoin 3.4 + 2.7% and of OH-phenobarbitone 1.4 ± 1.2%. No correlation was found between the recovery of OH-mephenytoin and OH-phenytoin. A subject who produced virtually no OH-phenytoin was an EM of mephenytoin, confirming a dissociation of mephenytoin polymorphism and phenytoin hydroxylation. 4 The correlation coefficient for OH-mephenytoin and OH-methylphenytoin recovery was 0.71 (Spearman rank, P = 0.002). The PMs of mephenytoin excreted the least amount of OH-methylphenytoin, suggesting a cosegregation of the 4-hydroxylation pathways. No correlation was found between the urinary recovery of OH-phenobarbitone and that of the other 4-hydroxy metabolites.Keywords mephenytoin polymorphism phenytoin methylphenytoin and phenobarbitone hydroxylation cytochrome P-450

(+)-N-3-Benzyl-Nirvanol and (−)-N-3-Benzyl-Phenobarbital: New Potent and Selective in Vitro Inhibitors of CYP2C19

“…Phenytoin is stereospecifically oxidized on the pro-(S)-phenyl ring by CYP2C9, whereas CYP2C19 exhibits low prochiral selectivity (Bajpai et al, 1996). However, if phenytoin is methylated at the N-3 position on the hydantoin ring, the resulting N-3-methyl-phenytoin is still metabolized by CYP2C19 but apparently is no longer a substrate for CYP2C9 (Schellens et al, 1990). Furthermore, it was demonstrated recently in vitro that (R)-mephobarbital, [(Ϫ)-N-3-methyl-phenobarbital] but not its (S)-antipode, is preferentially metabolized by CYP2C19 (Kobayashi et al, 2001).…”

Depression of phenytoin metabolic capacity by 5-fluorouracil and doxifluridine in rats

“…Separation of the metabolites, substrate and internal standard was performed on a Shim-pak CLC-ODS column (particle size 5 m, 150¬ 4.6 mm inner diameter ; Shimadzu) at ambient temperature. 5-(4-Hydroxyphenyl)-5-phenylhydan toin (4« -HPPH), the p-hydroxylated metabolite of phenytoin, was measured according to the procedure of Schellens et al (1990), using 50 % methanol (v}v, % ) as the mobile phase. The¯ow rate was set at 0.5 mL min 1 , and the column e‚ uent was monitored at 214 nm.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…CYP2C19 produces a quantitatively less important metabolite, R-HPPH, and reduced urinary elimination of this metabolite (but not of S-HPPH) is seen in CYP2C19 PMs (Fritz et al, 1987). Single-dose studies suggest no important influence of CYP2C19 metabolizer status on phenytoin metabolism (Schellens et al, 1990;Kerb et al, 2001), possibly reflecting the lack of CYP2C9 saturation with single doses. In contrast, population pharmacokinetic studies in Japanese and Taiwanese patients who were regularly administered phenytoin for epilepsy have demonstrated a slight reduction in V max and/or K m in the presence of CYP2C19 variants (Odani et al, 1997;Mamiya et al, 1998;Hung et al, 2004).…”