title: Effect of ABCG2 genotype on the oral bioavailability of topotecan.
abstract: ABCG2 (BCRP/MXR/ABCP) functions as an efflux transporter for many agents, including topotecan, and the protein is expressed at high levels in the human intestine. Some individuals possess a nonsynonymous variant in the ABCG2 gene at nucleotide 421, substituting lysine for glutamine on position 141 at exon 5. The present pilot study indicates that this genotype results in a 30% reduced efflux transport of topotecan in vitro compared to the wild-type. In a preliminary fashion, the heterozygous CA allele observed in two patients was associated with a 1.34-fold increased oral bioavailability of topotecan compared to the bioavailability in ten patients with the wild-type allele (42.0% versus 31.4%; p = 0.037). It is suggested that the high frequency of the A allele in certain ethnic groups may have therapeutic implications for individuals treated with topotecan or other ABCG2 substrates.
authors.affiliation: Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, Maryland, USA. w.loos@erasmusmc.nl
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Kees
authors.initials: K
authors.lastname: Nooter
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D018288:Carcinoma, Small Cell / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D010597:Pharmacogenetics; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D019772:Topotecan