To address the most appropriate endogenous biomarker for drug-drug interaction risk assessment, eight healthy subjects received an organic anion transporting polypeptide 1B (OATP1B) inhibitor (rifampicin, 150, 300, and 600 mg), and a probe drug cocktail (atorvastatin, pitavastatin, rosuvastatin, and valsartan). In addition to coproporphyrin I, a widely studied OATP1B biomarker, we identified at least 4 out of 28 compounds (direct bilirubin, glycochenodeoxycholate-3-glucuronide, glycochenodeoxycholate-3-sulfate, and hexadecanedioate) that presented good sensitivity and dynamic range in terms of the rifampicin dose-dependent change in area under the plasma concentration-time curve ratio (AUCR). Their suitability as OATP1B biomarkers was also supported by the good correlation of AUC0-24h between the endogenous compounds and the probe drugs, and by nonlinear regression analysis (AUCR-1 vs. rifampicin plasma Cmax (maximum total concentration in plasma)) to yield an estimate of the inhibition constant of rifampicin. These endogenous substrates can complement existing OATP1B-mediated drug-drug interaction risk assessment approaches based on agency guidelines in early clinical trials.

中文翻译：

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利福平在健康志愿者中对剂量依赖性的OATP1B抑制作用：候选生物标志物和OATP1B探针药物的综合评价。

为了解决用于药物-药物相互作用风险评估的最合适的内源性生物标志物，八名健康受试者接受了有机阴离子转运多肽1B（OATP1B）抑制剂（利福平，150、300和600 mg）和探针药物混合物（阿托伐他汀，匹伐他汀，瑞舒伐他汀和缬沙坦）。除了被广泛研究的OATP1B生物标志物卟啉I外，我们还从28种化合物中鉴定了至少4种（直接胆红素，糖基去氧胆酸盐3-葡糖醛酸，糖基去氧胆酸盐-3-硫酸盐和十六烷二酸酯），它们在以下方面表现出良好的灵敏度和动态范围：血浆浓度-时间曲线比率（AUCR）下利福平的剂量依赖性面积变化。内源性化合物与探针药物之间AUC0-24h的良好相关性也支持了它们作为OATP1B生物标志物的适用性，然后通过非线性回归分析（AUCR-1与利福平血浆Cmax（血浆中最大总浓度））得出利福平抑制常数的估算值。这些内源性底物可以在早期临床试验中根据机构指南补充现有的OATP1B介导的药物-药物相互作用风险评估方法。