Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals.

Hepatocyte nuclear receptor 4 alpha (HNF4 alpha) plays a central role in regulating human drug-metabolizing enzymes. Our previous study suggested that the newly identified polymorphism G60D in the HNF4a 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 (HNF4 alpha wild type: n = 24; HNF4 alpha G60D heterozygotes: n = 6) who were pregenotyped for CYP2D6. Our study showed HNF4 alpha G60D to be an independent predictor for increased AUC(0-infinity), C-max of tolterodine and increased AUC(0-infinity) of the active moiety (tolterodine + 5-hydroxymethyl-tolterodine) (P < 0.05). A significant proportion of the variance in these parameters (R-2 = 0.81, 0.59, and 0.63, respectively; P< 0.01) was explained together by CYP2D6 and HNF4 alpha genotypes. Further investigation of HNF4 alpha genetic polymorphisms may improve the predictability of CYP2D6 activity in different populations. Pharmacogenetics and Genomics 23:175-179 (c) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.