Renal Pharmacokinetic Adaptation to Cholestasis Causes Increased Nephrotoxic Drug Accumulation by Mrp6 Downregulation in Mice.

Abstract

In hepatic dysfunction, renal pharmacokinetic adaptation can be observed, although information on the changes in drug exposure and the interorgan regulation of membrane transporters in kidney in liver diseases is limited. This study aimed to clarify the effects of renal exposure to nephrotoxic drugs during cholestasis induced by bile duct ligation (BDL). Among the 11 nephrotoxic drugs examined, the tissue accumulation of imatinib and cisplatin in kidney slices obtained from mice 2 weeks after BDL operation was higher than that in sham-operated mice. The uptake of imatinib in the kidney slices of BDL mice was slightly higher, whereas its efflux from the slices was largely decreased compared to that in sham-operated mice. Proteomic analysis revealed a reduction in renal expression of the efflux transporter multidrug resistance-associated protein 6 (Mrp6/Abcc6) in BDL mice, and both imatinib and cisplatin were identified as Mrp6 substrates. Survival probability after cisplatin administration was reduced in BDL mice. In conclusion, the present study demonstrated that BDL-induced cholestasis leads to the downregulation of the renal basolateral efflux transporter Mrp6, resulting in drug accumulation in renal cells and promoting drug-induced renal injury.

• Authors: Hiroshi Arakawa, Takumi Kawanishi, Dai Shengyu, Takumi Nishiuchi, Makiko Meguro-Horike, Shin-Ichi Horike, Masahiro Sugimoto, Yukio Kato
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 112 Issue 12 Pg. 3209-3215 (12 2023) ISSN: 1520-6017 [Electronic] United States
• PMID: 37611664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Chemical References

• Imatinib Mesylate
• Cisplatin
• Membrane Transport Proteins
• Abcc6 protein, mouse
• Multidrug Resistance-Associated Proteins

Topics

• Mice
• Animals
• Liver (metabolism)
• Down-Regulation
• Imatinib Mesylate
• Cisplatin
• Proteomics
• Cholestasis (metabolism)
• Bile Ducts (metabolism, surgery)
• Liver Diseases (metabolism)
• Membrane Transport Proteins (metabolism)
• Kidney (metabolism)
• Multidrug Resistance-Associated Proteins (metabolism)