Tissue distribution of teneligliptin in rats and comparisons with data reported for other dipeptidyl peptidase-4 inhibitors.

We investigated the tissue distribution of teneligliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, in rats, and compared it with tissue distributions previously reported for other DPP-4 inhibitors. Following the oral administration of [14 C]teneligliptin to Sprague-Dawley rats, it was predominantly distributed to the kidney and liver, followed by the lung, spleen, and pituitary gland. The elimination half-life (t1/2 ) of [14 C]teneligliptin was 68.3 and 69.0 h in the kidney and liver, respectively; these values were about 10 times greater than the plasma t1/2 . Of note, the elimination of [14 C]teneligliptin from tissues with high DPP-4 activity (kidney, liver, and lung) was slower in wild-type rats than in DPP-4-deficient rats, especially in the kidney. By contrast, in the heart and pancreas, which weakly express DPP-4, we observed no difference in [14 C]teneligliptin concentrations between the two animal strains. In the kidney, most radioactivity was attributable to unchanged teneligliptin from 0.5 to 72 h after administration. The marked difference in the distribution of [14 C]teneligliptin between the two strains suggests that the high binding affinity of teneligliptin for DPP-4 is involved in its tissue distribution. The currently marketed DPP-4 inhibitors are highly distributed to the liver, kidney, and lung, but the extent of tissue distribution varies greatly among the drugs. The differences in the tissue distributions of DPP-4 inhibitors might be related to differences in their pleiotropic effects. This article is protected by copyright. All rights reserved.

Investigation of Potential Pharmacokinetic Interactions Between Teneligliptin and Metformin in Steady-state Conditions in Healthy Adults.

PURPOSE: We assessed the effects of coadministration of metformin and teneligliptin on their pharmacokinetics in steady-state conditions relative to the administration of either drug alone. METHODS: This was a Phase I, single-center, open-label, 2-way parallel-group study in healthy male and female subjects. Subjects in group 1 (n = 20) were administered 40 mg of teneligliptin once daily for 5 days, and 850 mg of metformin BID was added to ongoing teneligliptin for an additional 3 days. The subjects in group 2 (n = 20) were administered 850 mg of metformin BID for 3 days, and 40 mg of teneligliptin once daily was added to ongoing metformin for an additional 5 days. Pharmacokinetic outcomes were the AUC0-τ and Cmax of metformin and teneligliptin when administered alone or in combination. FINDINGS: Ten male and 10 female subjects participated in each group (mean ± SD age 39.2 ± 11.6 years [range, 19-63 years] in group 1, 47.6 ± 11.9 years [27-64] in group 2; mean ± SD BMI 23.36 ± 2.45 in group 1, 24.56 ± 2.54 in group 2). One female subject in each group was withdrawn because of an adverse event (AE) (vomiting). All 20 subjects in each group were included in the safety analyses, and 19 subjects in each group were included in the pharmacokinetic analyses. The geometric least square means ratio (teneligliptin plus metformin/teneligliptin alone) for Cmax and the AUC0-τ for teneligliptin were 0.907 (90% CI, 0.853-0.965) and 1.042 (90% CI, 0.997-1.089), respectively. The geometric least square means ratio (metformin plus teneligliptin/metformin alone) for the Cmax and AUC0-τ for metformin were 1.057 (90% CI, 0.974-1.148) and 1.209 (90% CI, 1.143-1.278). The 90% CIs were within the prespecified threshold for equivalence (0.80-1.25), except for the AUC0-τ for metformin, which was increased by teneligliptin by 20% relative to metformin alone. In group 1, nine subjects experienced 25 AEs during treatment with teneligliptin alone and 10 subjects experienced 15 AEs during treatment with teneligliptin plus metformin. In group 2, eight subjects experienced 11 AEs during treatment with metformin alone and 11 subjects experienced 18 AEs during treatment with metformin plus teneligliptin. Two AEs in each treatment group were rated as severe. Results of in vitro experiments suggest that teneligliptin-mediated inhibition of organic cation transporter-2 does not increase metformin exposure. IMPLICATIONS: Coadministration of teneligliptin and metformin was well tolerated by these healthy subjects during the 8-day treatment period. Coadministration with metformin did not affect the pharmacokinetics of teneligliptin. Although coadministration with teneligliptin increased exposure to metformin, this change is unlikely to be clinically relevant. European Clinical Trials Database identifier: 2007-001511-29.

Evaluation of the potency of telaprevir and its metabolites as inhibitors of renal organic cation transporters, a potential mechanism for the elevation of serum creatinine.

Telaprevir-based triple therapy is a highly effective treatment for chronic hepatitis C. However, adverse reactions include reversible and dose-dependent elevation of serum creatinine levels. We speculated that this effect reflects inhibition of the renal organic cation transporters hOCT2, hMATE1, and hMATE2-K by telaprevir or its metabolites (VRT-127394 and VRT-0922061). Telaprevir, VRT-127394, and VRT-0922061 showed negligible or weak effects on hOCT2 at concentrations of ≥20 µM, but inhibited hMATE1 by 35, 38, and 53% and hMATE2-K by 47, 45, and 61% at 100 µM, respectively. Telaprevir or its metabolites (10 µM) did not affect basal-to-apical transport of MPP(+) across monolayers of hOCT2-hMATE1 double-transfected MDCKII cells, whereas pyrimethamine, a potent inhibitor of hMATE1, markedly inhibited MPP(+) transport. Taken together, inhibition of hOCT2, hMATE1, and hMATE2-K is unlikely to be clinically relevant because unbound plasma concentrations of telaprevir and its metabolites reach only 2 µM following oral administration of a dose of 750 mg telaprevir. Hence, elevated serum creatinine during telaprevir therapy may not be related to direct inhibition of renal organic cation transporters.