The genetically controlled mephenytoin p(4′)‐hydroxylation capacity was determined in 118 Caucasians and 70 Orientals. After an oral dose of 50 or 100 mg of racemic mephenytoin, the amount of p(4′)‐ hydroxymephenytoin in 24 h urine was measured by gas chromatography. Bimodal distribution was found with 9/70 (13%) Orientals and 5/118 (4%) Caucasians demonstrating deficient p(4′)‐hydroxylation. The statistically significant difference between Orientals and Caucasians (P less than 0.05) was accounted for by the high incidence of poor metabolizers among the Japanese subjects, 7/31 (23%). The frequency among Chinese subjects, 2/39 (5%), was similar to the frequency among Caucasians.

The frequency of genetically deficient hydroxylation of mephenytoin (M-defect) was studied in 83 healthy Caucasians living in Toronto. The M-defect was compared with the widely studied genetic polymorphism of sparteine/debrisoquine oxidations (S-defect). After ingestion of mephenytoin and sparteine, urine samples (0 to 24 hr) were analyzed for p(4')-hydroxymephenytoin and urine samples over 0 to 12 hr were analyzed for sparteine and 2-and 5-dehydrosparteine by gas chromatographic methods. Nirvanol, the N-demethylation product of mephenytoin, was determined by a newly developed gas chromatographic/mass spectrometric method. Frequency distributions of both p-hydroxymephenytoin and dehydrosparteine excreted in urine were discontinuous (bimodal), while nirvanol and sparteine data were normally distributed. Two poor metabolizers of mephenytoin excreted 2% to 3% of the dose as p-hydroxymephenytoin and excreted normal amounts of nirvanol, but they were extensive metabolizers of sparteine. Six poor metabolizers of sparteine were found to be extensive metabolizers of mephenytoin (34% to 42% excreted in urine as p-hydroxyme-phenytoin). Thus the M-defect occurs among Canadian Caucasians with a frequency of 2% (0.0% to 7.5% with a confidence limit of 99%) and is independent of the S-defect.

Recent population data suggest independence of the genetic polymorphisms in mephenytoin and sparteine/debrisoquine oxidation. We used human liver preparations to test whether mephenytoin competes with sparteine for binding to the genetically variable cytochrome P-450, which mediates metabolism of both sparteine and debrisoquine. Mephenytoin failed to inhibit in vitro sparteine oxidation. This provides biochemical evidence that the polymorphism of sparteine/debrisoquine metabolism is not related to that of mephenytoin.

N-Glucosidation is a novel pathway of barbiturate metabolism, so far known to occur only in man. A search for an animal model, conducted through in vitro screening, revealed that amobarbital-N-glucoside was formed in liver preparations from the cat. The presence of amobarbital-N-glucoside was demonstrated in cat urine, following i.p. administration of amobarbital.

The disposition and metabolism of iodochlorhydroxyquin (clioquinol), an amebicidal drug with neurotoxic properties, were studied in dogs and rats with 14C-labelled drug. Pharmacokinetic studies in the dog demonstrated that the compound was well absorbed; the bioavailability was 36% of the dose of 1 mg/kg. The serum half-life was 1.3-1.8 h. In both the dog and the rat, biliary excretion was a major route of elimination. The dog excreted 27% of an intravenously administered dose (1 mg/kg) in the bile within 2 h; the rat excreted 39% of the dose (5 mg/kg i.v.) in less than 3 h. Elimination via the renal route was also substantial in both species. Urinary and biliary metabolites were separated by TLC (thin layer chromatography) and identified as sulfate and glucuronide conjugates in both species. No evidence for any other metabolites was found. A significant difference was observed between the dog and the rat in the extent of conjugation; the percentage radioactivity in the urine accounted for by the unchanged compound was six to twenty times greater for the dog than for the rat. The species differences in the disposition and metabolism of the compound might explain its greater toxicity in the dog than in the rat.