Koishikawa Tomoki, Fujiwara Kaku, Taskar Kunal, Zamek-Gliszczynski Maciej J, Yoshida Kenta, Chu Xiaoyan, Hirabayashi Hideki, Mao Jialin, Rockich Kevin, Takashima Tadayuki, Yamaura Yoshiyuki, Lai Yurong, Tomoda Yukana, Kito Tomoko, Maeda Kazuya, Furihata Kenichi, Sugiyama Yuichi, Kusuhara Hiroyuki
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo City, Japan.
Drug Metabolism and Pharmacokinetic, GSK, Stevenage, UK.
Clin Pharmacol Ther. 2025 Feb;117(2):523-533. doi: 10.1002/cpt.3482. Epub 2024 Nov 5.
This study was designed to assess the quantitative performance of endogenous drug-drug interaction (DDI) biomarkers (N1-methylnicotinamide (1-NMN), N1-methyladenosine (mA), and creatinine) for the organic cation transporters, OCT2 and MATE1/2K in the kidney. Ten healthy volunteers received cimetidine (400 and 800 mg, single dose) or dolutegravir (50 mg, twice a day) together with metformin (500 mg). Cimetidine and dolutegravir were considered to act mainly as MATE1/2K and OCT2 inhibitors, respectively. The renal clearance (CL) of metformin was decreased by 15.5% and 42.5% by cimetidine 400 and 800 mg, and by 26.8% and 56.9% by dolutegravir first and fifth doses, respectively. CL ratio (CLR) of 1-NMN were 0.93 and 0.64 for cimetidine 400 and 800 mg, and 0.87 and 0.47 for dolutegravir first and fifth doses, respectively. CLR of mA was less than that of 1-NMN: 1.0 and 0.80 for cimetidine 400 and 800 mg, and 0.77 and 0.71 for dolutegravir first and fifth doses, respectively. CL of creatinine was significantly decreased only by cimetidine 800 mg. Individual CLR of 1-NMN and mA showed a positive correlation with the corresponding CLR of metformin with r of 0.58 and 0.55, respectively. When evaluated individually, mA showed a better correlation during cimetidine periods (r 0.64) than 1-NMN (r 0.36), but vice versa during dolutegravir periods (r 1-NMN, 0.80; mA, 0.32). These results suggest that 1-NMN and mA might be more promising than creatinine as endogenous biomarkers for quantitatively assessing the DDI potential of investigational drugs for OCT2 and MATE1/2K based on their CLR change.
本研究旨在评估内源性药物 - 药物相互作用（DDI）生物标志物（N1 - 甲基烟酰胺（1 - NMN）、N1 - 甲基腺苷（mA）和肌酐）对肾脏中有机阳离子转运体OCT2和MATE1/2K的定量性能。10名健康志愿者接受西咪替丁（400和800mg，单次给药）或多替拉韦（50mg，每日两次）联合二甲双胍（500mg）治疗。西咪替丁和多替拉韦分别被认为主要作为MATE1/2K和OCT2抑制剂。400mg和800mg西咪替丁使二甲双胍的肾清除率（CL）分别降低了15.5%和42.5%，多替拉韦首剂和第五剂分别使其降低了26.8%和56.9%。400mg和800mg西咪替丁使1 - NMN的CL比值（CLR）分别为0.93和0.64，多替拉韦首剂和第五剂分别为0.87和0.47。mA的CLR低于1 - NMN：400mg和800mg西咪替丁分别为1.0和0.80，多替拉韦首剂和第五剂分别为0.77和0.71。仅800mg西咪替丁使肌酐的CL显著降低。1 - NMN和mA的个体CLR与二甲双胍相应的CLR呈正相关，r分别为0.58和0.55。单独评估时，在西咪替丁治疗期间mA显示出比1 - NMN更好的相关性（r 0.64对r 0.36），但在多替拉韦治疗期间则相反（r 1 - NMN，0.80；mA，0.32）。这些结果表明，基于CLR变化，1 - NMN和mA作为内源性生物标志物在定量评估研究药物对OCT2和MATE1/2K的DDI潜力方面可能比肌酐更有前景。
