The SLCO1B1 rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications
The SLCO1B1 rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications
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DOI：
10.1128/aac.01833-10
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发表时间：
2011-09-01
影响因子：
4.9
通讯作者：
McIlleron, Helen
中科院分区：
文献类型：
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作者：
Chigutsa, Emmanuel;Visser, Marianne E.;McIlleron, Helen
据报道，在结核病患者中，非洲人的利福平血浆浓度和痰菌转化率较低。利福平是P-糖蛋白（由ABCB 1基因编码）和有机阴离子转运多肽1B 1（由SLCO 1B 1编码）的底物。目的是确定药物转运蛋白和转录调节因子的遗传多态性，包括对南非人利福平药代动力学的影响，如PXR和CAR。来自开普敦的57例结核病患者在接受利福平、吡嗪酰胺、异烟肼和乙胺丁醇治疗期间进行药代动力学采样。使用实时PCR对DNA进行ABCB 1、SLCO 1B 1、PXR和CAR多态性基因分型。NONMEM用于数据分析。SLCO 1B 1 rs 4149032多态性的等位基因频率为0.70。该多态性的杂合子和纯合子患者的利福平生物利用度（以及曲线下面积[AUC]）分别降低了18%和28%。模拟结果显示，在具有多态性的患者中，每日利福平剂量增加150 mg将导致血浆浓度与野生型个体相似，并将血浆峰浓度（C（max））低于8 mg/L的患者百分比从63%降低至31%。ABCB 1、PXR和CAR多态性与利福平药代动力学差异无关。SLCO 1B 1 rs 4149032存在于大多数患者中，并与利福平暴露量大幅降低相关。这些数据表明，应该重新考虑南非人的利福平标准推荐剂量。
Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ABCB1 gene) and organic anion-transporting polypeptide 1B1 (coded for by SLCO1B1). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1, SLCO1B1, PXR, and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (C(max)) below 8 mg/liter from 63% to 31%. ABCB1, PXR, and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.