Premium
Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype
Author(s) -
Sparreboom Alex,
Gelderblom Hans,
Marsh Sharon,
Ahluwalia Ranjeet,
Obach Rosendo,
Principe Paola,
Twelves Chris,
Verweij Jaap,
McLeod Howard L.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.03.003
Subject(s) - pharmacokinetics , abcg2 , pharmacology , pharmacogenetics , genotype , cyp2d6 , clinical pharmacology , cyp3a4 , efflux , medicine , cytochrome p450 , cyp2c9 , transporter , atp binding cassette transporter , biology , metabolism , gene , genetics
Objective The adenosine triphosphate–binding cassette transporter ABCG2 (breast cancer resistance protein [BCRP]) functions as an efflux transporter for many drugs, including the topoisomerase I inhibitor diflomotecan, and is expressed at high levels in the intestine and liver. We performed an exploratory analysis to evaluate the effects of the natural allelic variant ABCG2 421C>A on the pharmacokinetics of diflomotecan. Methods The drug was administered to 22 adult white patients with cancer as a 20–minute infusion (dose, 0.10–0.27 mg), followed 2 weeks later by an oral solution (dose, 0.10–0.35 mg). Results The ABCG2 421C>A genotype significantly affected the pharmacokinetics of diflomotecan; in 5 patients heterozygous for this allele, plasma levels after intravenous drug administration were 299% ( P = .015) of those in 15 patients with wild–type alleles, at mean values of 138 ng · h/mL · mg −1 (95% confidence interval, 11.3–264 ng · h/mL · mg −1 ) versus 46.1 ng · h/mL · mg −1 (95% confidence interval, 25.6–66.7 ng · h/mL · mg −1 ), respectively. Diflomotecan levels were not significantly influenced by 11 known variants in the ABCB1 , ABCC2 , cytochrome P450 (CYP) 3A4, and CYP3A5 genes. Conclusion These findings provide the first evidence linking variant ABCG2 alleles to altered drug exposure and suggest that interindividual variability in substrate drug effects might be influenced, in part, by ABCG2 genotype. Clinical Pharmacology & Therapeutics (2004) 76 , 38–44; doi: 10.1016/j.clpt.2004.03.003