Disposition of debrisoquine and nortriptyline in Korean subjects in relation to CYP2D6 genotypes, and comparison with Caucasians

British Journal of Clinical Pharmacology
2003.0

Abstract

<jats:p><jats:bold>Aims </jats:bold> To study the influence of the <jats:italic>CYP2D6</jats:italic>*<jats:italic>10</jats:italic> allele on the disposition of debrisoquine and nortriptyline.<jats:p><jats:bold>Methods </jats:bold> The pharmacokinetics of debrisoquine and nortriptyline and their main metabolites were determined in ten Koreans with the <jats:italic>CYP2D6</jats:italic>*<jats:italic>1/</jats:italic>*<jats:italic>1</jats:italic> (<jats:italic>n</jats:italic> = 5) and <jats:italic>CYP2D6</jats:italic>*<jats:italic>1/</jats:italic>*<jats:italic>10</jats:italic> (<jats:italic>n</jats:italic> = 5) genotypes after single oral doses of 20 mg debrisoquine and 25 mg nortriptyline, respectively. The data were compared with previously published findings from 21 Caucasians with 0, one, two, three, four or 13 functional <jats:italic>CYP2D6</jats:italic> genes.<jats:p><jats:bold>Results </jats:bold> The AUC<jats:sub>0−8 </jats:sub>of 4‐hydroxydebrisoquine was significantly lower in Koreans with <jats:italic>CYP2D6</jats:italic>*<jats:italic>1/</jats:italic>*<jats:italic>10</jats:italic> genotype compared with <jats:italic>CYP2D6</jats:italic>*<jats:italic>1/</jats:italic>*<jats:italic>1</jats:italic>[95% confidence interval (CI) for the ratio between means 1.17, 1.85]. No other genotype‐related differences were found in the plasma kinetics of nortriptyline and debrisoquine, or their hydroxy metabolites. The AUC<jats:sub>nortriptyline</jats:sub>/AUC10‐hydroxynortriptyline ratio did not differ between the *<jats:italic>1/</jats:italic>*<jats:italic>1</jats:italic> and *<jats:italic>1/</jats:italic>*<jats:italic>10</jats:italic> genotype groups (95% CI for the ratio of means 0.60, 1.26). Similarly, there was no difference between these genotypes with respect to the AUC<jats:sub>debrisoquine</jats:sub>/AUC4‐hydroxydebrisoquine ratio (95% CI for the ratio of mean values 0.38, 1.46). Both Korean genotype groups had similar AUCs and parent compound/metabolite AUC ratios of debrisoquine and nortriptyline to Caucasians with two functional <jats:italic>CYP2D6</jats:italic> genes.<jats:p><jats:bold>Conclusions </jats:bold> Heterozygosity for <jats:italic>CYP2D6</jats:italic>*<jats:italic>10</jats:italic> decreases the CYP2D6‐dependent elimination of nortriptyline and debrisoquine to only a limited degree. Further studies in subjects homozygous for <jats:italic>CYP2D6</jats:italic>*<jats:italic>10</jats:italic> are required to elucidate fully the pharmacokinetic consequences of this <jats:italic>CYP2D6</jats:italic> genotype in Orientals.

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