Cancer Biology & Therapy · 2005 · 160 citations · 18 references
Veterinary MedicineGeneticsPharmacologyBioavailabilityPharmacogeneticsPharmacogenomicsDrug DispositionDrug Metabolism GeneticsDrug Transporter GeneticsGermline Pharmacogenetic VariationPharmacogenetic TestingTransporter PharmacologyAtp-binding Cassette Transporter PolymorphismsEfflux Transporter PolymorphismsIntestinal Drug EffluxIntestinal Efflux TransportersNonsynonymous MutationsOral Drug BioavailabilityPharmacokinetics Of Transporter VariantsVariants In Drug Transporters
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.
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