Tanaka Yuta, Kitamura Yoshiaki, Maeda Kazuya, Sugiyama Yuichi
Discovery Research Laboratories, Kyorin Pharmaceutical Company, Ltd, Tochigi, Japan.
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
J Pharm Sci. 2015 Sep;104(9):3039-48. doi: 10.1002/jps.24366. Epub 2015 Jan 30.
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.
ABCG2基因c.421C>A是ABCG2中最常见的多态性之一，ABCG2编码乳腺癌耐药蛋白（BCRP）。临床药物遗传学研究表明，口服BCRP底物药物后，c.421C>A多态性纯合子（421AA）受试者的血浆浓度-时间曲线下面积（AUC）值显著高于野生型受试者（421CC）。本研究的目的是基于临床药代动力学数据定量评估c.421C>A多态性导致的BCRP功能在体内的下降情况。假设药代动力学改变由肠道BCRP引起，通过比较肠道吸收模型的计算结果和临床药代动力学数据，优化突变型BCRP与野生型BCRP转运活性的比值。总之，估计421AA受试者体内肠道BCRP的转运活性约为421CC受试者的23%。
