Determinants of gefitinib pharmacokinetics in healthy Chinese male subjects: A pharmacogenomic study of cytochrome p450 enzymes and transporters.

What is known and objective Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, exhibited a wide interindividual variability in pharmacokinetics. In the present study, we aimed to evaluate the impact of single-nucleotide polymorphisms in the metabolizing enzymes and transporters on gefitinib disposition in healthy Chinese subjects. Methods Fourteen single-nucleotide polymorphisms, including polymorphisms of ATP-binding cassette (ABC) transporters and cytochrome P450 enzymes, were genotyped by Sanger sequencing, and the concentration of gefitinib was measured by ultrafast liquid chromatography-tandem mass spectrometry. The association between the pharmacokinetic parameters (peak plasma concentration [C-max], time to reach C-max, plasma half-life, area under the concentration-time curve from 0 to 168 hours [AUC((0-168h))], AUC((0-infinity))and plasma clearance [CL/F]) and genotypes was evaluated using unpairedttest or Mann-WhitneyUtest. A stepwise multiple linear regression analysis was applied to assess the relationships between multiple factors and gefitinib pharmacokinetics. Thirty-nine healthy Chinese male subjects were enrolled in the pharmacokinetic study. Results and discussion Subjects carrying an ABCG2 A allele (c.421CA + c.421AA genotypes) exhibited 33 and 37% increases in the mean gefitinib AUC((0-168h))and AUC((0-infinity))values (P < .05), respectively, compared to that of subjects carrying wild-type ABCG2 (c.421CC). Additionally, the mean CL/F of the c.421A allele carriers was 32% less than that of the c.421CC carriers (P < .05). No associations were found between polymorphisms in other metabolic enzymes or ABC transporters and gefitinib pharmacokinetics. What is new and conclusion Our results suggested that a single-nucleotide polymorphism inABCG2(c.421C>A) significantly affected the pharmacokinetics of gefitinib. Further studies are required to evaluate the effects of single-nucleotide polymorphism on the pharmacokinetics, pharmacodynamics and toxicity of gefitinib.