Effects of Cimetidine and Dolutegravir on the Endogenous Drug–Drug Interaction Biomarkers for Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Protein 1 in Healthy Volunteers
Tomoki Koishikawa, Kaku Fujiwara, Kunal S. Taskar, Maciej J. Zamek‐Gliszczynski, Kenta Yoshida, Xiaoyan Chu, Hideki Hirabayashi, Jialin Mao, Kevin Rockich, Tadayuki Takashima, Yoshiyuki Yamaura, Yurong Lai, Yukana Tomoda, Tomoko Kito, Kazuya Maeda, Kenichi Furihata, Yuichi Sugiyama, Hiroyuki Kusuhara
Abstract
This study was designed to assess the quantitative performance of endogenous drug–drug interaction (DDI) biomarkers ( N 1‐methylnicotinamide (1‐NMN), N 1‐methyladenosine (m 1 A), 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 r ) 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 r ratio (CL r R) 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. CL r R of m 1 A 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 r of creatinine was significantly decreased only by cimetidine 800 mg. Individual CL r R of 1‐NMN and m 1 A showed a positive correlation with the corresponding CL r R of metformin with r 2 of 0.58 and 0.55, respectively. When evaluated individually, m 1 A showed a better correlation during cimetidine periods ( r 2 0.64) than 1‐NMN ( r 2 0.36), but vice versa during dolutegravir periods ( r 2 1‐NMN, 0.80; m 1 A, 0.32). These results suggest that 1‐NMN and m 1 A 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 CL r R change.