Correlations among the metabolic ratios of three test probes (metoprolol, debrisoquine and sparteine) for genetically determined oxidation polymorphism in a Japanese population.

Abstract

The study was aimed at defining the relationships among the oxidative capacities for three prototype drugs, metoprolol, debrisoquine and sparteine, used for assessing genetically determined polymorphism of drug oxidation in a Japanese population. Among 292 unrelated healthy Japanese subjects who had been defined as extensive (EMs, n = 291) or poor (PM, n = 1) metabolisers of metoprolol oxidation, 55 subjects (EMs = 54 and PM = 1) were selected. One PM of metoprolol oxidation was also identified as a PM not only of debrisoquine but also of sparteine, and no misclassification by the three phenotypic methods was observed. All three correlations among the metabolic ratios of the three test probes assessed by Spearman's rank test were highly significant (P < 0.001). These findings indicate that in Japanese subjects the oxidation capacities of metoprolol, debrisoquine, and sparteine are closely related. It appears that in Japanese the polymorphic oxidation of the three drugs is co-regulated, either by the same enzyme or gene-controlling system.

Metabolic ratios of four probes of CYP2D6 in Turkish subjects: A cross-over study

“…In Caucasian populations there was no dissociation of metabolic capacities for CYP2D6 probes when two drugs were used (1). Japanese populations also show complete concordance in their ability to metabolize three probe drugs such as debrisoquine, sparteine and metoprolol (2). In contrast to these results, there was a dissociation of the control of debrisoquine, sparteine and metoprolol oxidation in African populations (8)(9)(10)(11).…”

“…The incidence of a defective liver debrisoquine 4-hydroxylase (CYP2D6) is about 3-10% in North American and European populations(I), whereas it is 0.3% in a Japanese population (2). Recently, the frequency of poor metabolizer (PM) of debrisoquine was found to be 3.4% in a Turkish population (3).…”

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

“…Sometimes, age-related changes and/ or diurnal-related changes in the stereoselective renal elimination of the parent and/or the metabolite may confound the MR calculations. Although not essential, it may be a good practice to reconfirm the phenotype data using two substrates of CYP2D6 for both chiral and nonchiral drugs (Droll et al, 1998;Horai et al, 1990). The evidence that variable urinary pH has the potential to compromise the MR of partially ionizable, lipid-soluble probe substrates further supports the above view point of having an alternate CYP2D6 enzymic activity monitoring strategy (Ozdemir et al, 2004).…”

Relationship between Serum Aprindine Concentration and Neurologic Side Effects in Japanese

“…10,11,13) As shown in Fig. 1, a poor positive correlation was observed between dose (mg/kg) and serum aprindine concentration, and it was tendency that the pharmacokinetics of apindine were nonlinear within the therapeutic range of serum concentrations.…”

“…Intermediator and ultra-rapid metabolizers of CYP2D6 are included in the same group as extensive metabolizers. 10,11) Therefore, drugs catalyzed by CYP2D6 have large interindividual variation.…”