Cyclosporine A sterically inhibits statin transport by solute carrier OATP1B1

• Published in: The Journal of biological chemistry Vol. 301; no. 5; p. 108484
• Main Authors: Sung, Min Woo, Hu, Kuan, Hurlimann, Lea M., Lees, Joshua A., Fennell, Kimberly F., West, Mark A., Costales, Chester, Rodrigues, Amilcar David, Zimmermann, Iwan, Dawson, Roger J.P., Liu, Shenping, Han, Seungil
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2025; American Society for Biochemistry and Molecular Biology
• Subjects: Atorvastatin - chemistry; Atorvastatin - metabolism; Biological Transport - drug effects; cryo-electron microscopy; Cyclosporine - chemistry; Cyclosporine - metabolism; Cyclosporine - pharmacology; drug transport; HEK293 Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism; Liver-Specific Organic Anion Transporter 1 - antagonists & inhibitors; Liver-Specific Organic Anion Transporter 1 - chemistry; Liver-Specific Organic Anion Transporter 1 - genetics; Liver-Specific Organic Anion Transporter 1 - metabolism; membrane protein; organic anion channel; transporter; OCT; FDA; OAT; ADME; DCF; drug transport; OATP; DDIs; transporter; EMA; membrane protein; MFS; organic anion channel; cryo-EM; cryo-electron microscopy
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2025.108484

Members of the Organic Anion Transporter Polypeptides (OATP) are integral membrane proteins responsible for facilitating the transport of organic anions across the cell membrane. OATP1B1 (SLCO1B1), the prototypic OATP family member, is the most abundant uptake transporter in the liver and a key mediator of the hepatic uptake and clearance of numerous endogenous and xenobiotic compounds. It serves as a locus of important drug-drug interactions, such as those between statins and cyclosporine A, and carries the potential to enable liver-targeting therapeutics. In this study, we report cryo-EM structures of OATP1B1 and its complexes with one of its statin substrates, atorvastatin, and an inhibitor, cyclosporine A. This structural analysis has yielded insights into the mechanisms underlying the OATP1B1-mediated transport of statins and the inhibitory effect of cyclosporine A. These findings contribute to a better understanding of the molecular processes involved in drug transport and offer potential avenues for the development of targeted medications for liver-related conditions.