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.

Abstract

This study was designed to assess the quantitative performance of endogenous drug-drug interaction (DDI) biomarkers (N1-methylnicotinamide (1-NMN), N1-methyladenosine (m¹A), 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_rR) 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_rR of m¹A 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_rR of 1-NMN and m¹A showed a positive correlation with the corresponding CL_rR of metformin with r² of 0.58 and 0.55, respectively. When evaluated individually, m¹A showed a better correlation during cimetidine periods (r² 0.64) than 1-NMN (r² 0.36), but vice versa during dolutegravir periods (r² 1-NMN, 0.80; m¹A, 0.32). These results suggest that 1-NMN and m¹A 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_rR change.