RGED RGED / Renal pharmacokinetic adaptation to cholestasis leads to increased accumulation of nephrotoxic drugs due to ABCC6 downregulation in mice

Public on 2022-08-29

Description

The liver plays a central role in the enzymatic metabolism and biliary excretion of drugs. In hepatic dysfunction, renal pharmacokinetic adaption could be observed, although information on the change of drug exposure and the interorgan regulation of membrane transporters in the kidney under liver diseases is limited. The present study aims to clarify renal exposure to nephrotoxic drugs during cholestasis induced by bile duct ligation (BDL). Among 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 ones. Moreover, the renal distribution of imatinib in BDL mice after intravenous administration was 16-times higher than that in sham-operated ones, whereas the plasma concentration-time profile was comparable between the two groups. The uptake of imatinib in the kidney slices of BDL mice was slightly higher, while its efflux from the slices was largely decreased compared with sham-operated ones. Proteomic analysis revealed a reduction in BDL mice of renal expression of an efflux transporter multidrug resistance-associated protein 6 (Mrp6/Abcc6), and both imatinib and cisplatin were clarified to be Mrp6 substrates. The survival probability after cisplatin administration was reduced in BDL mice. In addition, microarray and metabolome analyses revealed a change in the metabolic pathway of both fat-soluble vitamins and amino acids by BDL, which may be associated with the exacerbated cisplatin-induced nephrotoxicity and/or the Mrp6 downregulation. In conclusion, the present study demonstrated that BDL-induced cholestasis leads to downregulation of the renal basolateral efflux transporter Mrp6, resulting in drug accumulation in renal cells and promoting drug-induced renal injury. This finding would be useful knowledge in possible renal adaption to cholestatic patients.

Overall Design

Comparison between bile duct ligation (BDL) and sham operations. There are two biological replicates for each condition.

Curator

yq_pan

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