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 [Cmax], time to reach Cmax, plasma half‐life, area under the concentration‐time curve from 0 to 168 hours [AUC(0‐168h)], AUC(0‐∞) and plasma clearance [CL/F]) and genotypes was evaluated using unpaired t test or Mann‐Whitney U test. 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‐∞) values (P A influence pharmacokinetics of gefitin