Maraviroc is a substrate for OATP1B1 in vitro and maraviroc plasma concentrations are influenced by SLCO1B1 521 T>C polymorphism
Maraviroc is a substrate for OATP1B1 in vitro and maraviroc plasma concentrations are influenced by SLCO1B1 521 T>C polymorphism
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Maraviroc 是 OATP1B1 的体外底物，Maraviroc 血浆浓度受 SLCO1B1 521 T>C 多态性影响
DOI：
10.1097/fpc.0b013e3283402efb
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发表时间：
2010
影响因子：
2.6
通讯作者：
A. Owen
中科院分区：
文献类型：
--
作者：
M. Siccardi;A. D’Avolio;S. Nozza;M. Simiele;L. Baietto;F. Stefani;D. Moss;W. Kwan;A. Castagna;A. Lazzarin;A. Calcagno;S. Bonora;D. Back;G. di Perri;A. Owen
有机阴离子转运多肽（oops）正成为许多药物药代动力学的主要决定因素，其中1B1异构体介导肝脏摄取。521t>c多态性早前就与几种药物的高血浆浓度相关，本研究的目的是确定这种多态性是否会影响马拉维洛克的血药浓度。方法采用异种非洲爪蟾卵母细胞表达系统评价OATP1B1对马拉韦洛克的摄取，采用新型液相色谱-质谱联用方法定量。对59例每日两次接受马拉维洛克150,300或600mg治疗的患者进行回归分析，以确定与马拉维洛克治疗相关的因素。结果确定马拉韦洛克为OATP1B1的底物，Km为33.9 mol/l。剂量为600mg依曲维林或依非韦伦[优势比(or)=0.22, 95%可信区间（95% CI）： 0.06-0.76；P=0.016]和SLCO1B1 521杂合度均与马洛维洛克浓度相关，高于建议的目标浓度50 ng/ml （OR=20.3, 95% CI: 2.2 ~ 182； P=0.007）。结论ooatp1b1在马拉韦洛克药代动力学变异性中的重要作用。此外，SLCO1B1 521 T>C多态性可能有助于预测较高的血浆浓度，但这些数据应在前瞻性临床研究确定临床实用性之前得到证实。
Background Organic anion transporting polypeptides (OATPs) are emerging as major determinants of pharmacokinetics for numerous drugs, with the 1B1 isoform-mediating hepatic uptake. The 521 T>C polymorphism has been correlated earlier with higher plasma concentrations of several drugs and the aim of this study was to determine whether this polymorphism influences trough concentrations of maraviroc. Methods The uptake of maraviroc by OATP1B1 was assessed using a heterologous Xenopus laevis oocyte expression system and quantified using a novel liquid chromatography-mass spectrometry method. Regression analyses were conducted to identify factors associated with maraviroc Ctrough in 59 patients treated with maraviroc at 150, 300, or 600 mg twice daily. Results Maraviroc was identified as a substrate for OATP1B1 with a Km of 33.9 &mgr;mol/l. A dose of 600 mg of etravirine or efavirenz [odds ratio (OR)=0.22, 95% confidence interval (95% CI): 0.06–0.76; P=0.016] and SLCO1B1 521 heterozygosity were both associated with maraviroc Ctrough, above the suggested target concentration of 50 ng/ml (OR=20.3, 95% CI: 2.2–182; P=0.007). Conclusion These findings show the importance of OATP1B1 for variability in maraviroc pharmacokinetics. Furthermore, the SLCO1B1 521 T>C polymorphism maybe useful in predicting higher plasma concentrations but these data should be confirmed before prospective clinical studies to define the clinical usefulness.