title: Pharmacokinetics of tolterodine in Japanese and Koreans: physiological and stochastic assessment of ethnic differences.
abstract: Tolterodine is known as a drug which exhibits ethnic differences in pharmacokinetics between Japanese and Koreans despite genetic similarities among the populations of East Asian countries. Tolterodine is mainly metabolized by CYP2D6 to a 5-hydroxymethyl metabolite (5-HM), and 5-HM is also metabolized by CYP2D6. The reduced-function allele CYP2D6*10 is frequently observed in Asian populations. We investigated differences in the pharmacokinetics of tolterodine between small Japanese and Korean study populations by physiological and stochastic approaches with consideration of the CYP2D6 genotype. The genotype frequencies of CYP2D6*10/*10 and CYP2D6*5/*10 were found to be higher in Koreans than in Japanese, which suggested that this frequency difference occurred incidentally. The effects of CYP2D6 genotype and ethnicity on the intrinsic clearance of tolterodine by CYP2D6 were tested and only genotype was found to be a significant factor by ANCOVA. A simulation was conducted to confirm whether the observed differences in tolterodine exposure could be explained by the differences in genotype frequency found in this study. It was confirmed that the variability of intrinsic clearance could be responsible for the incidental exposure differences. In conclusion, apparent differences in exposure were found between small Japanese and Korean study populations because of the variability of intrinsic clearances and genotype frequencies.
authors.affiliation: Department of Drug Development Science & Clinical Evaluation, Keio University of Pharmacy, Tokyo, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Oishi
authors.forename: Koji
authors.initials: K
authors.lastname: Chiba
authors.forename: Bimal
authors.initials: B
authors.lastname: Malhotra
authors.forename: Toshio
authors.initials: T
authors.lastname: Suwa
mesh_terms: D000328:Adult; D019540:Area Under Curve; D044466:Asian People / Q000208:ethnology* / Q000235:genetics*; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D003198:Computer Simulation; D003408:Cresols / Q000378:metabolism / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005006:Ethnicity; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D007564:Japan / Q000208:ethnology; D007723:Korea / Q000208:ethnology; D008297:Male; D008954:Models, Biological; D010665:Phenylpropanolamine / Q000378:metabolism / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic / Q000502:physiology*; D000068737:Tolterodine Tartrate; D055815:Young Adult
chemical_list: C109909:5-hydroxymethyl tolterodine; D001559:Benzhydryl Compounds; D003408:Cresols; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D019389:Cytochrome P-450 CYP2D6