Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype

摘要: Objective The adenosine triphosphate–binding cassette transporter ABCG2 (breast cancer resistance protein [BCRP]) functions as an efflux for many drugs, including the topoisomerase I inhibitor diflomotecan, and is expressed at high levels in intestine liver. We performed exploratory analysis to evaluate effects of natural allelic variant 421C>A on pharmacokinetics diflomotecan. Methods The drug was administered 22 adult white patients with a 20–minute infusion (dose, 0.10–0.27 mg), followed 2 weeks later by oral solution 0.10–0.35 mg). Results The genotype significantly affected diflomotecan; 5 heterozygous this allele, plasma after intravenous administration were 299% (P = .015) those 15 wild–type alleles, mean values 138 ng · h/mL mg−1 (95% confidence interval, 11.3–264 mg−1) versus 46.1 25.6–66.7 mg−1), respectively. Diflomotecan not influenced 11 known variants ABCB1, ABCC2, cytochrome P450 (CYP) 3A4, CYP3A5 genes. Conclusion These findings provide first evidence linking alleles altered exposure suggest that interindividual variability substrate might be influenced, part, genotype. Clinical Pharmacology & Therapeutics (2004) 76, 38–44; doi: 10.1016/j.clpt.2004.03.003