Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan (T.N.) and Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan (T.K., K.I.).
Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan (T.N.) and Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan (T.K., K.I.)
Drug Metab Dispos. 2023 Sep;51(9):1114-1126. doi: 10.1124/dmd.122.000969. Epub 2023 Mar 1.
Creatinine is a common biomarker of renal function and is secreted in the renal tubular cells via drug transporters, such as organic cation transporter 2 and multidrug and toxin extrusion (MATE) 1/2-K. To differentiate between drug-induced acute kidney injury (AKI) and drug interactions through the renal transporter, it has been examined whether these transporter inhibitions quantitatively explained increases in serum creatinine (SCr) at their clinically relevant concentrations using drugs without any changes in renal function. For such renal transporter inhibitors and recently approved tyrosine kinase inhibitors (TKIs), this mini-review describes clinical increases in SCr and inhibitory potentials against the renal transporters. Most cases of SCr elevations can be explained by considering the renal transporter inhibitions based on unbound maximum plasma concentrations, except for drugs associated with obvious changes in renal function. SCr increases for cobicistat, dolutegravir, and dronedarone, and some TKIs were significantly underestimated, and these underestimations were suggested to be associated with low plasma unbound fractions. Sensitivity analysis of SCr elevations regarding inhibitory potentials of MATE1/2-K demonstrated that typical inhibitors such as cimetidine, DX-619, pyrimethamine, and trimethoprim could give false interpretations of AKI according to the criteria based on relative or absolute levels of SCr elevations. Recent progress and current challenges of physiologically-based pharmacokinetics modeling for creatinine disposition were also summarized. Although it should be noted for the potential impact of in vitro assay designs on clinical translatability of transporter inhibitions data, mechanistic approaches could support decision-making in clinical development to differentiate between AKI and creatinine-drug interactions. SIGNIFICANCE STATEMENT: Serum creatinine (SCr) is widely used as an indicator of kidney function, but it increases due to inhibitions of renal transporters, such as multidrug and toxin extrusion protein 1/2-K despite no functional changes in the kidney. Such SCr elevations were quantitatively explained by renal transporter inhibitions except for some drugs with high protein binding. The present analysis demonstrated that clinically relevant inhibitors of the renal transporters could cause SCr elevations above levels corresponding to acute kidney injury criteria.
肌酸酐是肾功能的常见生物标志物，通过药物转运体（如有机阳离子转运体 2 和多药和毒素外排（MATE）1/2-K）在肾小管细胞中分泌。为了区分药物引起的急性肾损伤（AKI）和通过肾脏转运体的药物相互作用，已经研究了在没有任何肾功能变化的情况下，这些转运体抑制剂在其临床相关浓度下是否可以定量解释血清肌酸酐（SCr）的增加。对于这些肾脏转运体抑制剂和最近批准的酪氨酸激酶抑制剂（TKIs），本综述描述了 SCr 的临床增加和对肾脏转运体的抑制潜力。除了与肾功能明显变化相关的药物外，考虑基于未结合最大血浆浓度的肾脏转运体抑制作用，可以解释大多数 SCr 升高的情况。考比司他、多替拉韦和多非利特的 SCr 升高以及一些 TKI 的抑制作用被显著低估，这些低估被认为与低血浆未结合分数有关。基于 MATE1/2-K 抑制潜力的 SCr 升高的敏感性分析表明，根据相对或绝对 SCr 升高水平的标准，西咪替丁、DX-619、乙胺嘧啶和甲氧苄啶等典型抑制剂可能会对 AKI 产生错误的解释。还总结了基于生理的药代动力学模型对肌酸酐处置的最新进展和当前挑战。虽然应该注意体外测定设计对转运体抑制作用数据临床转化性的潜在影响，但机制方法可以支持临床开发中的决策制定，以区分 AKI 和肌酸酐-药物相互作用。意义陈述：血清肌酸酐（SCr）被广泛用作肾功能的指标，但由于肾脏转运体的抑制作用，如多药和毒素外排蛋白 1/2-K，即使肾脏没有功能变化，SCr 也会增加。除了一些与蛋白结合率高的药物外，这些 SCr 升高可以通过肾脏转运体抑制作用来定量解释。目前的分析表明，临床相关的肾脏转运体抑制剂可导致 SCr 升高超过急性肾损伤标准对应的水平。
