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

被引：76

作者：

Mizuno, Tomoyuki ^{[1
]}

Fukudo, Masahide ^{[1
]}

Terada, Tomohiro ^{[1
]}

Kamba, Tomomi ^{[2
]}

Nakamura, Eijiro ^{[2
]}

Ogawa, Osamu ^{[2
]}

Inui, Ken-ichi ^{[1
]}

Katsura, Toshiya ^{[1
]}

机构：

[1] Kyoto Univ Hosp, Dept Pharm, Kyoto 606, Japan

[2] Kyoto Univ, Grad Sch Med, Dept Urol, Kyoto, Japan

来源：

DRUG METABOLISM AND PHARMACOKINETICS | 2012年 / 27卷 / 06期

关键词：

ABCG2; ABCB1; transporter; pharmacogenetics; pharmacogenomics; tyrosine kinase inhibitor; RENAL-CELL CARCINOMA; SINGLE-NUCLEOTIDE POLYMORPHISMS; P-GLYCOPROTEIN; MDR1; GENE; TRANSPLANT RECIPIENTS; C3435T POLYMORPHISM; INTERFERON-ALPHA; PHASE-I; ABCG2; EXPRESSION;

D O I：

10.2133/dmpk.DMPK-12-RG-026

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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(-/-), Abcbla/1b(-/-) and Abcbla/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 ABCBI (1236C>T, 2677G>T/A and 3435C>T) were examined. The dose-adjusted AUC(0-24) 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 AUC(0-24). The ABCB1 polymorphisms were not associated with the dose-adjusted AUC(0-24). The maximum concentration and AUC(0-4) of sunitinib were significantly higher in Abcg2(-/-), Abcbla/1b(-/-) and Abcbla/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.

引用

页码：631 / 639

页数：9

共 42 条

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