Mirogabalin, a novel α₂δ ligand, is not a substrate of LAT1, but of PEPT1, PEPT2, OAT1, OAT3, OCT2, MATE1 and MATE2-K

Abstract

1. Mirogabalin is a α₂δ ligand as well as pregabalin. The aim of this study was to clarify whether mirogabalin is a substrate of human LAT1, which involved in absorption and disposition of pregabalin, and to investigate transporters involved in renal secretion and absorption of mirogabalin using transporter-expressing cells and fresh human kidney slices.

2. We employed uptake assay of [³H]mirogabalin by HEK293T or HEK293 cells transiently overexpress human OAT1, OAT3, OCT2, LAT1/4F2hc, LAT2/4F2hc, PEPT1, and PEPT2 proteins. Transport assay of MDCKII cells transiently overexpress OCT2/MATE1, and OCT2/MATE2-K proteins was conducted. Contribution of transporters to renal secretion was investigated by uptake assay using human kidney slices.

3. Uptake clearances of [³H]mirogabalin by OAT1-, OAT3-, OCT2-, PEPT1-, and PEPT2-expressing cells were higher than that by vector cells, but by LAT1/4F2hc and LAT2/4F2hc-expressing cells were not. In transport assay using OCT2/MATE1 and OCT2/MATE2-K cells, [³H]mirogabalin showed directional transport from basolateral to apical side. Contribution of OAT1, OAT3, and OCT2 was observed by uptake of [³H]mirogabalin into the kidney slices.

4. These results indicate that mirogabalin is not a substrate of LAT1, but of PEPT1 and PEPT2 involved in absorption and of OAT1, OAT3, OCT2, MATE1 and/or MATE2-K involved in its urinary secretion.

Keywords:

• Mirogabalin
• urinary excretion
• active secretion
• organic anion transporter
• organic cation transporter
• multidrug and toxin extrusion protein
• human

Acknowledgments

The author thanks Krisztina Szirtes (Solvo Biotechnology) and Gábor Imre (Solvo Biotechnology at the time of the study) for conducting permeability experiments using MATE1, MATE2-K and OCT2 double-transfected MDCKII cell monolayers and Rie Komura and Haruna Fujiwara for conducting uptake experiments using other transporters expressing cells.

Disclosure statement

N. Yamamura, T. Mikkaichi, K. Itokawa, M. Hoshi, K. Damme, S. Geigner, and C. Baumhauer are full-time employees of the sponsor, Daiichi Sankyo Co., Ltd. The authors report no declarations of interest.