Regular Article
Impact of Genetic Variation in Breast Cancer Resistance Protein (BCRP/ABCG2) on Sunitinib Pharmacokinetics

https://doi.org/10.2133/dmpk.DMPK-12-RG-026Get rights and content

Summary:

To elucidate the impact of genetic variations in breast cancer resistance protein (BCRP/ ABCG2) and P-glycoprotein (MDR1/ABCB1) on the pharmacokinetics of sunitinib, we carried out a pharmacogenetic study in a clinical setting and pharmacokinetic analysis using Abcg2−/−, Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice. Nineteen renal cell carcinoma patients were enrolled in this study. The plasma concentrations of sunitinib and its active metabolite were determined and the area under the concentration- time curve (AUC) was calculated. Genetic polymorphisms in ABCG2 (421C > A) and ABCB1 (1236C > T, 2677G > T/A and 3435C > T) were examined. The dose-adjusted AUC0–24 of sunitinib was significantly higher in patients with a heterozygous variant for ABCG2 421C > A than in wild-type patients (p = 0.02), and one homozygous patient showed the highest dose-adjusted AUC0–24. The ABCB1 polymorphisms were not associated with the dose-adjusted AUC0–24. The maximum concentration and AUC0–4 of sunitinib were significantly higher in Abcg2−/−, Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice than wild-type mice when sunitinib was given orally but not intraperitoneally. Incidence of thrombocytopenia and hypertension and poor compliance were associated with the systemic exposure to sunitinib and its active metabolite. These results suggest that the loss of protein expression of ABCG2 by genetic polymorphism is associated with an increase in the systemic exposure to sunitinib and sunitinib-induced toxicity.

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      As this transporter was first identified in the context of chemotherapy, the irinotecan metabolite SN-38, topotecan, and doxorubicin are examples for BCRP substrates [53]. Also newer drugs like the tyrosine-kinase inhibitor sunitinib are both substrates and inhibitors of BCRP, as it has been shown in humans [54], in rat experiments using pantoprazole as an inhibitor of BCRP [55] and in cells overexpressing BCRP [56]. However, it has to be acknowledged that the impact of hepatic BCRP on the overall pharmacokinetics of BCRP substrates cannot readily be estimated, because BCRP is also present in the intestines and the kidneys, where the effect of BCRP on the pharmacokinetics of drugs is probably much larger than at the canalicular side of liver cells.

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    This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. T. Mizuno is a Research Assistant in the Global COE Program “Center for Frontier Medicine.”

    Present address: Department of Pharmacy, Shiga University Medical Science of Hospital, Seta Tsukinowa-cho, Otsu 520–2192, Japan.

    ††

    Present address: Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashina-ku, Kyoto 607–8414, Japan.

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