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J Pharm Sci. 2015 Sep;104(9):3039-48. doi: 10.1002/jps.24366. Epub 2015 Jan 30.

Quantitative Analysis of the ABCG2 c.421C>A Polymorphism Effect on In Vivo Transport Activity of Breast Cancer Resistance Protein (BCRP) Using an Intestinal Absorption Model.

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Discovery Research Laboratories, Kyorin Pharmaceutical Company, Ltd, Tochigi, Japan.
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, Yokohama, Japan.


ABCG2 c.421C>A is one of the most frequent polymorphisms in ABCG2, which encodes the breast cancer resistance protein (BCRP). Clinical pharmacogenetic studies have shown that the plasma area under the concentration-time curve (AUC) values after oral administration of BCRP substrate drugs are significantly higher in subjects homozygous for the c.421C>A polymorphism (421AA) than in wild-type subjects (421CC). The aim of this study was to quantitatively estimate the in vivo decrease of BCRP function caused by the c.421C>A polymorphism based on clinical pharmacokinetic data. Assuming that the pharmacokinetic alteration is accounted for by intestinal BCRP, the ratio of the transport activity of the mutated BCRP to that of the wild-type was optimized by comparing calculations from an intestinal absorption model and clinical pharmacokinetic data. In conclusion, the in vivo intestinal BCRP transport activity in 421AA subjects is estimated to be approximately 23% of that in the 421CC subjects.


ABC transporters; intestinal absorption; mathematical model; pharmacogenetics; pharmacokinetics

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