Quantitative Estimation of Catechol/Methylcatechol Pathways in Human Phenytoin Metabolism

Abstract

A gas-liquid chromatographic (GLC) assay utilizing an on-column methylation technique has been developed to assay urinary concentration of a phenytoin (5,5-diphenylhydantoin, PHT) metabolite, 5-(4-hydroxy-3-methoxyphenyl)-5-phenylhydantoin (MCAT). Assay of MCAT in 35 24-h urine samples from patients receiving chronic phenytoin (PHT) therapy indicated that 0.3-4.0% of the daily dose could be accounted for as MCAT. The GLC assay was specific for MCAT, and provided a minimal estimate of the fraction of the PHT dose being metabolized via the catechol/MCAT route. Multiple regression analyses indicated that the amount of urinary MCAT was dependent on the quantities of both dihydrodiol (DHD) and p-phenolic (p-HPPH) metabolites. Oxidative pathways involving both DHD and p-HPPH as substrates appear to be responsible for catechol/MCAT production.

Polymorphisms of human cytochrome P450 2C9 and the functional relevance

“…It exhibits nonlinear pharmacokinetics in humans. Following oral administration, four oxidative metabolites, S-5-(4p-hydroxyphenyl)-5-phenylhydantoin (4 -HPPH), 3 -HPPH, 3 ,4 -diHPPH, and 3 ,4 -dihydrodiol, have been identified in humans (Maguire, 1988). Phenytoin is mainly oxidized to 4 -HPPH by CYP2C9 and to a minor extent by CYP2C19 (Bajpai et al, 1996).…”

The clinical impact of cytochrome P450 polymorphisms on anti-epileptic drug therapy

“…Seventy to 90% of orally administrated phenytoin is oxidized mainly by CYP2C9, and to a minor extent by CYP2C19, to yield S-5-(4p-hydroxyphenyl)-5-phenylhydantoin in humans [27,28]. The relative contribution of CYP2C19 in phenytoin metabolism increases as phenytoin concentrations increase, leading to saturation of CYP2C9 [28].…”

Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries

“…1) (Maguire, 1988;Szabo et al, 1990;Komatsu et al, 2000). The studies using cDNAexpressed P450 enzymes have revealed that 4'-hydroxy DPH (4'-HPPH), which is the major metabolite of DPH identified in humans and rats, was formed by CYP2C9-and CYP2C11-mediated metabolism in humans (Komatsu et al, 2000) and rats (Yamazaki et al, 2001), respectively.…”