Pharmacogenetics of mephenytoin: A new drug hydroxylation polymorphism in man

Abstract

Inherited deficiency in mephenytoin hydroxylation was observed in a family study. It is important that the propositus was of the extensive metabolizer phenotype for the genetically controlled hydroxylation of debrisoquine. Thus, a genetic polymorphism of drug hydroxylation was suspected for mephenytoin. A population study of mephenytoin hydroxylation, combined with identification of extensive and poor debrisoquine hydroxylation phenotypes, was carried out in 221 unrelated normal volunteers. Twelve of them (5%) exhibited defective aromatic hydroxylation of mephenytoin, and 23 (10%) could be identified as poor metabolizers of debrisoquine. Amongst these 35 subjects with a drug hydroxylation deficiency, 3 (or 0.5%; 1 female, 2 males) displayed both defects simultaneously. A panel study of 10 extensive and 10 poor metabolizers of mephenytoin showed that the ability to perform aromatic hydroxylation of the demethylated mephenytoin metabolite nirvanol (5-phenyl-5-ethylhydantoin) was co-inherited with the mephenytoin hydroxylation polymorphism. Family studies suggested that poor metabolizer phenotypes of nirvanol and mephenytoin were most likely to have the homozygous genotype for an autosomal recessive allele of deficient aromatic drug hydroxylation. Intra-subject comparison of the debrisoquine and mephenytoin hydroxylation phenotypes in these subjects indicated that deficiency in the two drug hydroxylations occurred independently. Consequently, the co-inheritance of extensive and poor hydroxylation of mephenytoin and nirvanol, respectively, represents a new drug hydroxylation polymorphism in man.

Testing for bimodality in frequency distributions of data suggesting polymorphisms of drug metabolism‐histograms and probit plots.

“…Although several authors (Kupfer & Preisig, 1984;Nakamura et al, 1985;Penno & Vesell, 1983) have considered that the position of the antimode within a bi-modal distribution is indicated by a sharp breakpoint in a probit plot, we have shown that this is not the case. The existence of a sharp breakpoint will depend upon the relative variances of the component distributions and its position will not coincide with that of the antimode (Figure 2e, f).…”

Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2‐receptor antagonist

“…42,45 Now these results can be clearly explained by interethnic variations in the CYP2C19 genotype. Among North American and European populations, 56.7-81.0% of patients are homo-EMs, 18.0-37.2% are hetero-EMs, and PMs are less than 6.1%, [46][47][48][49][50] and thus omeprazole 40 mg is required to achieve stronger gastric acid suppression than H 2 -RAs. However, in Orientals, homo-EMs are only 27.7-38.2% and the rest of the population has an intermediate or reduced capacity to metabolize omeprazole; 30,[51][52][53] and therefore strong gastric acid suppression can be obtained even with omeprazole 20 mg or less.…”

Genetic analysis of the cytochrome P‐450IIC18 (CYP2C18) gene and a novel member of the CYP2C subfamily

“…The human CYP2C subfamily consists of at least 4 members (CYP2C8, CYP2C9, CYP2C18, CYP2C19) [1,2]. Extensive metabolizer (EM) and poor metabolizer (PM) polymorphism for mephenytoin [3,4] is well known and has been studied extensively. It has been shown that CYP2C19 is a candidate for mephenytoin 4'-hydroxylation [5,6].…”