Article

Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype.

Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD 20892, USA.
Clinical Pharmacology &#38 Therapeutics (impact factor: 6.04). 07/2004; 76(1):38-44. DOI:10.1016/j.clpt.2004.03.003 pp.38-44
Source: PubMed

ABSTRACT 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.
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).
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.
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.

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Keywords

15 patients
 
2 weeks
 
20-minute infusion
 
22 adult white patients
 
5 patients heterozygous
 
ABCG2 genotype
 
adenosine triphosphate-binding cassette transporter ABCG2
 
breast cancer resistance protein [BCRP]
 
CYP3A5 genes
 
Diflomotecan levels
 
drug exposure
 
exploratory analysis
 
first evidence
 
interindividual variability
 
intravenous drug administration
 
natural allelic variant ABCG2 421C>A
 
plasma levels
 
substrate drug effects
 
variant ABCG2 alleles
 
wild-type alleles