Renal tubular transporter-mediated interactions between mirogabalin and cimetidine in rats
Creators: name: Yamamura, Naotoshi
name: Imaoka, Tomoki
name: Hoshi, Misa
name: Yamada, Makiko
name: Itokawa, Ken-ichi
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Space Science
subject: Medicine
subject: Molecular Biology
subject: Neuroscience
subject: Physiology
subject: FOS: Biological sciences
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: Marine Biology
subject: 60506 Virology
subject: Computational Biology

description: 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 <i>in vivo</i>.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 [<sup>14</sup>C]metformin, [<sup>3</sup>H]<i>p</i>-aminohippuric acid (PAH), and [<sup>14</sup>C]mirogabalin.Cimetidine significantly induced the intrarenal accumulation of radioactivity (Kp, kidney) and decreased the renal clearance (CLr) of [<sup>14</sup>C]mirogabalin. These effects resulted in significantly decreased total clearance (CLt). Kp, kidney, and CLr of [<sup>14</sup>C]metformin, except CLt, were also affected, but no parameters of [<sup>3</sup>H]PAH were affected by cimetidine.These findings clarified that an unbound plasma concentration of cimetidine of 7.0 μM inhibited the apical efflux not the basolateral uptake of [<sup>14</sup>C]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. 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 <i>in vivo</i>. 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 [<sup>14</sup>C]metformin, [<sup>3</sup>H]<i>p</i>-aminohippuric acid (PAH), and [<sup>14</sup>C]mirogabalin. Cimetidine significantly induced the intrarenal accumulation of radioactivity (Kp, kidney) and decreased the renal clearance (CLr) of [<sup>14</sup>C]mirogabalin. These effects resulted in significantly decreased total clearance (CLt). Kp, kidney, and CLr of [<sup>14</sup>C]metformin, except CLt, were also affected, but no parameters of [<sup>3</sup>H]PAH were affected by cimetidine. These findings clarified that an unbound plasma concentration of cimetidine of 7.0 μM inhibited the apical efflux not the basolateral uptake of [<sup>14</sup>C]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.