Renal tubular transporter-mediated interactions between mirogabalin and cimetidine in rats

Abstract

1. Cimetidine at a clinical dosage decreased the renal clearance (CLr) of mirogabalin in humans by inhibition of renal secretion. Mirogabalin is a substrate of human OAT1/3, OCT2, MATE1 and/or MATE2-K. To clarify the mechanism behind the above interaction, it was investigated whether cimetidine inhibits the process of mirogabalin uptake at the basolateral side or the process of its efflux at the apical side in rat kidney in vivo.

2. Cimetidine was administered to rats by a constant infusion to achieve an unbound plasma concentration of 7.0 μM and examine its effect on the renal disposition of [¹⁴C]metformin, [³H]p-aminohippuric acid (PAH), and [¹⁴C]mirogabalin.

3. Cimetidine significantly induced the intrarenal accumulation of radioactivity (Kp, kidney) and decreased the renal clearance (CLr) of [¹⁴C]mirogabalin. These effects resulted in significantly decreased total clearance (CLt). Kp, kidney, and CLr of [¹⁴C]metformin, except CLt, were also affected, but no parameters of [³H]PAH were affected by cimetidine.

4. These findings clarified that an unbound plasma concentration of cimetidine of 7.0 μM inhibited the apical efflux not the basolateral uptake of [¹⁴C]mirogabalin in rat kidney, suggesting that mirogabalin/cimetidine interaction was caused by inhibiting the apical efflux transporter, human MATE1 and/or MATE2-K, not the basolateral uptake transporter, human OCT2, in the kidney.

Keywords:

• Mirogabalin
• kidney
• secretion
• urinary excretion
• cimetidine
• inhibition
• rat Oct2
• rat Mate1

Acknowledgements

The authors thank Tsuyoshi Mikkaichi (Daiichi Sankyo Co., Ltd) for discussions on the experimental design.

Disclosure statement

N. Yamamura, T. Imaoka, M. Hoshi, M. Yamada, and K. Itokawa are full-time employees of the sponsor, Daiichi Sankyo Co., Ltd.

Additional information

Funding

This work was funded by Daiichi Sankyo Co., Ltd.