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


Pharmacogenet Genomics. 2013 Jan 2;


Authors: Jiang F, Yeo CW, Lee SS, Oh MK, Ghim JL, Shon JH, Kim HS, Kim EY, Kim DH, Shin JG


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-∞, Cmax 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.

PMID: 23292115 [PubMed - as supplied by publisher]