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.

Figure 1

Effect of dolutegravir on OCT2‐, MATE1‐, and MATE2‐K mediated uptake of metformin. The uptake of metformin (10 μM) in the absence and presence of dolutegravir (0.1–30 μM for OCT2, and 0.3–100 μM for MATE1) was determined for 2 and 5 minutes at 37°C in OCT2‐, MATE1‐, and MATE2‐K‐HEK, respectively. The K _i values of dolutegravir were determined by non‐linear regression analysis, assuming that IC50 can approximate K _i when the substrate concentrations were sufficiently lower than the K_m values. The rigid lines represent fitted lines. The previously determined K _i values were also plotted for comparison. They were obtained from the DIDB® (CERTARA, Radnor, PA). The dotted and dashed lines represent the C _max,u of dolutegravir at fifth and first doses, respectively.

Figure 2

Plasma concentration time profiles of each drug and X _urine and CL_r of metformin. (a) Plasma concentrations of cimetidine (400 and 800 mg, po) and dolutegravir (50 mg BID) were shown. Time 0 represented the time at which metformin was administered. Cimetidine or dolutegravir was administered 1 hour before the administration of metformin. The plasma concentrations of dolutegravir at 12, 24, 48, and 60 hours represent the trough concentrations, and the last sampling time point was 72 hours. Each symbol and vertical bar represents the arithmetic mean and SEM. (b) Plasma concentration‐time profile of metformin with or without cimetidine or dolutegravir‐treatments are shown. Each symbol and error bar represents the arithmetic mean and SEM, respectively. Amounts of urinary excretion (X _urine) at each urine collection interval were shown. Each bar and vertical bar represents the mean and SEM. Box‐and‐whisker plots of the CL_r of metformin is shown. The subject numbers: n = 10 control and cimetidine‐treated group; n = 9 dolutegravir‐treated group.

Figure 3

Effects of cimetidine and dolutegravir on the plasma concentrations, X _urine and CL_r of 1‐NMN (a), m¹A (b) and creatinine (c). Plasma concentration‐time profiles of metformin with or without cimetidine or dolutegravir were shown. Each symbol and error bar represents the mean and SEM, respectively. Amounts of urinary excretion (X _urine) at each urine collection interval were shown. Each bar and vertical bar represents the mean and SEM. Box‐and‐whisker plots of the CL_r of metformin is shown. The subject numbers: n = 10 control and cimetidine‐treated group; n = 9 dolutegravir‐treated group.

Figure 4

AUC ratio and CL_r ratio of metformin and the endogenous substrates. The geometric mean ratios of AUC and CL_r with 90% confidence intervals were shown.

Figure 5

Correlation CL_rR (a) and AUCR (b) between metformin and endogenous biomarkers. The correlation of CL_rR (a) and AUCR (b) among the test compounds were shown with correlation coefficients and P values. Each symbol represents an individual data point.