Gessner Arne, Müller Fabian, Wenisch Pia, Heinrich Markus R, König Jörg, Stopfer Peter, Fromm Martin F
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Clin Pharmacol Ther. 2023 Nov;114(5):1058-1072. doi: 10.1002/cpt.3017. Epub 2023 Aug 18.
Endogenous biomarkers are discussed as tools for detection of drug-drug interactions (DDIs) mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2-K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intra-study comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of 10 previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with 4 inhibitors of transport proteins [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N-oxide were both sensitive and specific (median log2-fold changes -1.18 in estimated renal elimination and -0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2-fold changes -3.77 and -2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid, and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE- and OAT-mediated DDIs.
内源性生物标志物被视为检测由肾转运蛋白介导的药物相互作用（DDIs）的工具，这些肾转运蛋白包括有机阳离子转运体2（OCT2）、多药及毒素外排蛋白（MATE1和MATE2-K）以及有机阴离子转运体（OAT1和OAT3）。虽然一些内源性生物标志物对至少一种临床转运体抑制剂的敏感性已被频繁证实，但研究中常常缺乏对抑制剂对不同生物标志物影响程度的内部比较。此外，此类讨论的生物标志物的体内特异性也常常未被研究。因此，我们研究了10种先前描述的推测的OCT2/MATEs抑制生物标志物以及15种先前描述的推测的OATs生物标志物在健康志愿者的人血浆和尿液样本中，对4种转运蛋白抑制剂[维拉帕米（P-糖蛋白）、利福平（有机阴离子转运多肽）、西咪替丁（OCT2/MATEs）和丙磺舒（OATs）]治疗的反应变化。其中有两种推测的生物标志物被认为与OCT2/MATEs和OATs都有关。在非靶向代谢组学分析中明确鉴定了所有物质。OCT2/MATE生物标志物胆碱和氧化三甲胺既敏感又具有特异性（估计肾清除率的中位log2倍变化分别为-1.18，尿排泄的中位log2倍变化为-0.85）。对于肾OATs，吲哚乙酰谷氨酰胺和吲哚乙酸（估计肾清除率的中位log2倍变化分别为-3.77和-2.85）是变化最广泛的敏感且特异的生物标志物候选物，其次是牛磺酸、吲哚乳酸和次黄嘌呤。这项全面的研究进一步增加了对23种先前描述的肾OCT2/MATE和OAT介导的DDIs生物标志物的敏感性和特异性的认识。
