Polyethlyene Glycol 200 Can Protect Rats Against Drug-Induced Kidney Toxicity Through Inhibition of the Renal Organic Anion Transporter 3

Yi-Zhong Gu; Xiaoyan Chu; Robert Houle; Katerina Vlasakova; Kenneth A Koeplinger; Isabelle Bourgeois; Kiran Palyada; Kenneth D Anderson; Christopher Brynczka; Bhavana Bhatt; Feifei Chen; Roger Smith; Rupesh Amin; Warren E Glaab; Jose Lebron; Kathleen Cox; Frank D Sistare

doi:10.1093/toxsci/kfz186

Polyethlyene Glycol 200 Can Protect Rats Against Drug-Induced Kidney Toxicity Through Inhibition of the Renal Organic Anion Transporter 3

Toxicol Sci. 2019 Nov 1;172(1):155-166. doi: 10.1093/toxsci/kfz186.

Authors

Yi-Zhong Gu¹, Xiaoyan Chu², Robert Houle², Katerina Vlasakova¹, Kenneth A Koeplinger², Isabelle Bourgeois^{1

3}, Kiran Palyada¹, Kenneth D Anderson², Christopher Brynczka¹, Bhavana Bhatt¹, Feifei Chen¹, Roger Smith¹, Rupesh Amin¹, Warren E Glaab¹, Jose Lebron¹, Kathleen Cox², Frank D Sistare¹

Affiliations

¹ Safety Assessment and Laboratory Animal Resources.
² Pharmacokinetics, Pharmacodynamics and Metabolism.
³ MSD, Riom 63963, France.

PMID: 31406999
DOI: 10.1093/toxsci/kfz186

Abstract

MK-7680, a cyclic nucleotide prodrug, caused significant kidney tubule injury in female rats when administered orally at 1000 mg/kg/day for 2 weeks using 10% Polysorbate 80 as vehicle. However, kidney injury was absent when MK-7680 was administered at the same dose regimen using 100% Polyethylene Glycol 200 (PEG 200) as the vehicle. Subsequent investigations revealed that MK-7680 triphosphate concentrations in kidney were much lower in rats treated with MK-7680 using PEG 200 compared with 10% Polysorbate 80 vehicle, whereas plasma exposures of MK-7680 prodrug were similar. In vitro studies demonstrated that PEG 200 is an inhibitor of human renal uptake transporter organic anion transporter 3 (OAT3), of which MK-7680 is a substrate. Furthermore, PEG 200 and PEG 400 were found to interfere in vitro with human renal transporters OAT3, organic cation transporter (OCT) 2, multidrug resistance-associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2K, but not OAT1. These results support a conclusion that PEG 200 may prevent MK-7680-induced kidney injury by inhibiting its active uptake into proximal tubular cells by OAT3. Caution should be exercised therefore when using PEGs as vehicles for toxicity assessment for compounds that are substrates of renal transporters.

Keywords: PEG 200; nephrotoxicity; renal transporters.