Phenotyping polymorphic drug metabolism in the French Caucasian population

Abstract

Because of the large interethnic differences in the incidence of poor metabolizer phenotypes, French Caucasians have been studied for two independent polymorphisms, debrisoquine/dextromethorphan and mephenytoin metabolism. One hundred and thirty-two unrelated French Caucasians were phenotyped using oral doses of dextromethorphan 20 mg and mephenytoin 100 mg. Individual dextrorphan excretion over 8 h and the dextromethorphan/dextrorphan metabolic ratio were calculated. Extensive metabolizers were taken as subjects with a high dextrorphan output (15.56 mumol/8 h) and a low metabolic ratio (0.0023), and poor metabolizers were those with a low dextrorphan output (0.39 mumol/8 h) and a high metabolic ratio (7.00). Individual 4-hydroxymephenytoin excretion and mephenytoin hydroxylation indices were also determined. Extensive metabolizers eliminated large amounts of 4 hydroxymephenytoin (133.2 mumol/8 h) and had a hydroxylation index of 1.99, and poor metabolizers, because of impaired mephenytoin metabolism, had a high hydroxylation index (277). The incidence of the poor metabolizer phenotype was 3% for dextromethorphan (95% confidence limits 0.5%-8.5%) and 6% for mephenytoin (95% confidence limits 2%-12.5%).

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.…”

Pharmacokinetic evaluation of proguanil: a probe phenotyping drug for the mephenytoin hydroxylase polymorphism

“…Metabolic pathway for proguanil oxidation to mephenytoin [11][12][13][14] they have been poorly validated. In Australia, ruc-mephenytoin as Mesantoin@ tablets (Sandoz) is no longer marketed due to (i) poor sales figures and (ii) the propensity for blood dyscrasias in a small proportion of the population [l5].…”

DNA haplotype dependency of debrisoquine 4-hydroxylase (CYP2D6) expression among extensive metabolisers

“…The polymorphism of debrisoquine/sparteine oxidation has been extensively investigated (Maghoub et al 1977;Jacqz et al 1988;Brosen and Gram 1990;Eichelbaum and Gross 1990). The poor metaboliser (PM) phenotype, affecting 5-10% of Caucasians, is due to the absence of a specific cytochrome P450, named CYP2D6.…”