Representative Rodent Models for Renal Transporter Alterations in Human Nonalcoholic Steatohepatitis.

Autor:	Frost KL; College of Pharmacy, Department of Pharmacology & Toxicology (K.L.F., J.L.J., E.L.T., N.J.C.) and College of Medicine, Department of Physiology (S.H.W.), The University of Arizona, Tucson, Arizona and Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey (M.J.G.)., Jilek JL; College of Pharmacy, Department of Pharmacology & Toxicology (K.L.F., J.L.J., E.L.T., N.J.C.) and College of Medicine, Department of Physiology (S.H.W.), The University of Arizona, Tucson, Arizona and Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey (M.J.G.)., Toth EL; College of Pharmacy, Department of Pharmacology & Toxicology (K.L.F., J.L.J., E.L.T., N.J.C.) and College of Medicine, Department of Physiology (S.H.W.), The University of Arizona, Tucson, Arizona and Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey (M.J.G.)., Goedken MJ; College of Pharmacy, Department of Pharmacology & Toxicology (K.L.F., J.L.J., E.L.T., N.J.C.) and College of Medicine, Department of Physiology (S.H.W.), The University of Arizona, Tucson, Arizona and Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey (M.J.G.)., Wright SH; College of Pharmacy, Department of Pharmacology & Toxicology (K.L.F., J.L.J., E.L.T., N.J.C.) and College of Medicine, Department of Physiology (S.H.W.), The University of Arizona, Tucson, Arizona and Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey (M.J.G.)., Cherrington NJ; College of Pharmacy, Department of Pharmacology & Toxicology (K.L.F., J.L.J., E.L.T., N.J.C.) and College of Medicine, Department of Physiology (S.H.W.), The University of Arizona, Tucson, Arizona and Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey (M.J.G.) cherring@pharmacy.arizona.edu.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Aug; Vol. 51 (8), pp. 970-981. Date of Electronic Publication: 2023 May 03.
DOI:	10.1124/dmd.122.001133
Abstrakt:	Alterations in renal elimination processes of glomerular filtration and active tubular secretion by renal transporters can result in adverse drug reactions. Nonalcoholic steatohepatitis (NASH) alters hepatic transporter expression and xenobiotic elimination, but until recently, renal transporter alterations in NASH were unknown. This study investigates renal transporter changes in rodent models of NASH to identify a model that recapitulates human alterations. Quantitative protein expression by surrogate peptide liquid chromatography-coupled mass spectrometry (LC-MS/MS) on renal biopsies from NASH patients was used for concordance analysis with rodent models, including methionine/choline deficient (MCD), atherogenic (Athero), or control rats and Lepr db/db MCD ( db/db ), C57BL/6J fast-food thioacetamide (FFDTH), American lifestyle-induced obesity syndrome (ALIOS), or control mice. Demonstrating clinical similarity to NASH patients, db/db, FFDTH, and ALIOS showed decreases in glomerular filtration rate (GFR) by 76%, 28%, and 24%. Organic anion transporter 3 (OAT3) showed an upward trend in all models except the FFDTH (from 3.20 to 2.39 pmol/mg protein), making the latter the only model to represent human OAT3 changes. OAT5, a functional ortholog of human OAT4, significantly decreased in db/db, FFDTH, and ALIOS (from 4.59 to 0.45, 1.59, and 2.83 pmol/mg protein, respectively) but significantly increased for MCD (1.67 to 4.17 pmol/mg protein), suggesting that the mouse models are comparable to human for these specific transport processes. These data suggest that variations in rodent renal transporter expression are elicited by NASH, and the concordance analysis enables appropriate model selection for future pharmacokinetic studies based on transporter specificity. These models provide a valuable resource to extrapolate the consequences of human variability in renal drug elimination. SIGNIFICANCE STATEMENT: Rodent models of nonalcoholic steatohepatitis that recapitulate human renal transporter alterations are identified for future transporter-specific pharmacokinetic studies to facilitate the prevention of adverse drug reactions due to human variability. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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