PII-54CYP3A5 but not CYP2D6 polymorphism affects dextropropoxyphene disposition in human subjects

Abstract

BACKGROUND The metabolism of dextropropoxyphene (DEX) to its major metabolite nordextropropoxyphene has been reported to be mediated via CYP2D6 and 3A in in vitro studies. In this study we evaluated the relative effect of CYP2D6, 3A4 and 3A5 polymorphism on DEX disposition in human subjects. METHODS Fourteen healthy male subjects received a single 32.5 mg DEX and 325 mg paracetamol (Cosalgesic tablet). Multiple blood samples were collected over 24h, and plasma concentrations of DEX and paracetamol were determined by an LC-MS-MS method. CYP2D6, 3A4 and 3A5 genotyping were performed using the respective PCR-RFLP analysis. RESULTS No CYP3A4 mutant alleles (*4, *5 and *6) were detected. There were no significant differences in DEX pharmacokinetics among subjects with different CYP2D6 genotype (ANOVA p>0.05). However, DEX plasma concentration was significantly higher in CYP3A5*3/*3 (n=8) than *1/*3 (n=5) or *1/*1 (n=1) subjects, and their respective apparent oral clearance were 2.26±0.93, 3.60±1.56, and 12.5 L/h/kg (ANOVA p<0.05). The pharmacokinetics of paracetamol was similar among subjects with different CYP2D6 or 3A5 genotypes. CONCLUSIONS CYP3A5 but not 2D6 polymorphism appears to exert a significant influence on DEX disposition. Subjects with CYP3A5*1/*1 genotype may be “ultrarapid” metabolizers of DEX, which could possibly lead to accumulation of toxic nordextropropoxyphene in the body. Further studies with larger number of subjects are needed to verify these findings. Clinical Pharmacology & Therapeutics (2005) 79, P50–P50; doi: 10.1016/j.clpt.2005.12.179