Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2004-07

AUTHORS

Alex Sparreboom, Hans Gelderblom, Sharon Marsh, Ranjeet Ahluwalia, Rosendo Obach, Paola Principe, Chris Twelves, Jaap Verweij, Howard L. McLeod

ABSTRACT

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 x h/mL x mg(-1) (95% confidence interval, 11.3-264 ng x h/mL x mg(-1)) versus 46.1 ng x h/mL x mg(-1) (95% confidence interval, 25.6-66.7 ng x h/mL x 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. More... »

PAGES

38-44

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1016/j.clpt.2004.03.003

DOI

http://dx.doi.org/10.1016/j.clpt.2004.03.003

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008182929

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/15229462


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