Estimation of the interindividual variability of cytochrome 2D6 activity from urinary metabolic ratios in the literature.
Cytochrome P450 2D6 (CYP2D6) is an enzyme with a large interindividual variability in its metabolic activity due to genetic polymorphisms. In the present study, both its intrinsic metabolic activity (CL(int,CYP2D6,app)) relative to extensive metabolizers (EM) and its variability were estimated by analyzing the urinary metabolic ratios (MR) based on the well-stirred model. Sparteine and debrisoquine were considered to be appropriate probes for our methodology, whereas dextromethorphan was not appropriate since the formation of its metabolite of interest is not described by the well-stirred model. From the analysis of MRs of sparteine and debrisoquine for Caucasian subjects in the literature, CL(int,CYP2D6,app) for intermediate metabolizers (IM) was estimated to be approximately 15% of that for EM. The coefficient of variability (CV) of CL(int,CYP2D6,app) was estimated to be approximately 60% for both EM and IM and 100% for the combined population of ultrarapid metabolizer, EM and IM [i.e., the non-poor metabolizer (non-PM) population]. Simulation of exposure in the non-PM population showed that the CV of exposure was 140% for dextromethorphan and 71% for metoprolol, which reflected the reported values of 110% and 53% for dextromethorphan and metoprolol, respectively. The present study should be useful for predicting the interindividual variability in exposure to investigational drugs that are metabolized by CYP2D6.
Ito
Takashi
T
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, japan. ito.takashi.uh@daiichisankyo.co.jp
Kato
Motohiro
M
Chiba
Koji
K
Okazaki
Osamu
O
Sugiyama
Yuichi
Y
D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D003915:Dextromethorphan / Q000493:pharmacokinetics; D006801:Humans; D008657:Metabolic Clearance Rate / Q000502:physiology; D008954:Models, Biological; D009010:Monte Carlo Method; D004364:Pharmaceutical Preparations / Q000378:metabolism* / Q000652:urine; D010641:Phenotype; D013034:Sparteine / Q000493:pharmacokinetics; D014556:Urine / Q000737:chemistry*
D004364:Pharmaceutical Preparations; D013034:Sparteine; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6