title: Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals.
abstract: Hepatocyte nuclear receptor 4α (HNF4α) plays a central role in regulating human drug-metabolizing enzymes. Our previous study suggested that the newly identified polymorphism G60D in the HNF4α gene may decrease its downstream CYP2D6 activity in Asians. To confirm this effect in a clinical setting, we carried out a full pharmacokinetic study of a single oral dose of CYP2D6 substrate tolterodine in 30 healthy Korean individuals (HNF4α wild type: n = 24; HNF4α G60D heterozygotes: n = 6) who were pregenotyped for CYP2D6. Our study showed HNF4α G60D to be an independent predictor for increased AUC0-∞, C max of tolterodine and increased AUC0-∞ of the active moiety (tolterodine+5-hydroxymethyl-tolterodine) (P<0.05). A significant proportion of the variance in these parameters (R = 0.81, 0.59, and 0.63, respectively; P<0.01) was explained together by CYP2D6 and HNF4α genotypes. Further investigation of HNF4α genetic polymorphisms may improve the predictability of CYP2D6 activity in different populations.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Fen
authors.initials: F
authors.lastname: Jiang
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Yeo
authors.forename: Sang-Seop
authors.initials: SS
authors.lastname: Lee
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Oh
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Ghim
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Shon
authors.forename: Ho-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D001559:Benzhydryl Compounds / Q000493:pharmacokinetics*; D003408:Cresols / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics*; D010665:Phenylpropanolamine / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D056910:Republic of Korea; D013379:Substrate Specificity; D000068737:Tolterodine Tartrate
chemical_list: D001559:Benzhydryl Compounds; D003408:Cresols; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D019389:Cytochrome P-450 CYP2D6