Effect of ABCG2 genotype and mRNA expression on the bioavailability of topotecan

Abstract

2015 Background: The ATP-binding cassette transporter ABCG2 (breast cancer resistance protein; BCRP) functions as an efflux transporter for many drugs and is expressed at high levels in the human small intestine. It has been demonstrated that some individuals possess a nonsynonymous single-nucleotide polymorphism at nucleotide 421, substituting lysine for glutamine on position 141 at exon 5, and express low amounts of ABCG2. Methods: In this prospective exploratory study, duodenal biopsies were obtained before oral administration of topotecan on day 1 (dose, 2.3 mg/m²) and i.v. infusion on day 2 (dose, 1.5 mg/m²) in 18 adult Caucasian cancer patients (10 female/8 male; median age, 54 years). Pharmacokinetic data were obtained on days 1 and 2. Topotecan concentrations in plasma were determined by liquid chromatography with fluorescence detection, and analyzed by noncompartmental methods. Enterocyte (villin)-corrected mRNA expression levels of ABCG2 and ABCB1 (P-glycoprotein) were measured by real-time TaqMan analysis, and all patients were genotyped by cycle sequencing for ABCG2 421C>A. Results: Complete topotecan pharmacokinetic data were available for 13 patients. The mean (± SD) area under the curves after oral and i.v. administration were 109 ± 35.7 ng×h/mL and 218 ± 62.3 ng×h/mL, respectively. Substantial intra- and interindividual variation in mRNA expression of ABCG2 and ABCB1 was observed in the intestinal samples (N = 12). Two patients were heterozygous variant for ABCG2421C>A (14%; allele frequency, 7.14%), and 12 patients carried the wild-type sequence; 4 samples showed no amplification. The heterozygous CA allele was associated with a 1.3-fold increased oral bioavailability of topotecan [31.4% (wild-type, N = 10) versus 42.0% (heterozygous, N = 2); P = 0.037]. The lowest combined mRNA expression of ABCG2 and ABCB1 was observed in one of the patients that was heterozygous variant for ABCG2 421C>A. Conclusions: This pilot study indicates that ABCG2 genotype is correlated with altered topotecan pharmacokin-etics. The current observation warrants confirmation and further investigation in a larger patient population involving different ethnic groups. No significant financial relationships to disclose.