PHARMACOLOGY

Nathan CHERRINGTON

SITE

Our group has made significant strides in identifying liver-specific disturbances in the expression and function of drug transporters and biotransformation enzymes. These molecular alterations lead to in vivo perturbations in the disposition of numerous xenobiotics. Therefore, we show that patients with Non-Alcoholic Fatty Liver Diseases present as a subpopulation of individuals who are at high risk for developing adverse drug effects, due to aberrant disposition of drugs and other xenobiotics. Specifically, our group has documented individual differences of metabolising enzymes and transporters with severe alterations in the pharmacokinetics, tissue concentrations, and toxicity of clinically relevant drugs and xenobiotics.

Drug Metab Dispos. 2022;In press. Renal transporter alterations in patients with chronic liver diseases: Nonalcoholic Steatohepatitis, alcohol-associated, viral hepatitis, and alcohol-viral combination. Frost KL, Jilek JL, Sinari S, Klein RR, Billheimer D, Wright SH, Cherrington NJ. PubMed

Toxicol Sci. 2022;189:62-72. Increased renal expression of complement components in patients with liver diseases: Nonalcoholic Steatohepatitis, Alcohol-associated, Viral Hepatitis, and Alcohol-Viral Combination. Frost KL, Jilek JL, Thompson AD, Klein RR, Sinari S, Torabzedehkorasani E, Billheimer DD, Schnellmann RG, Cherrington NJ. PubMed

Acta Pharm Sin B. 2021;11:3869-3878.Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity. Jilek JL, Frost KL, Jacobus KA, He W, Toth EL, Goedken M, Cherrington NJ. PubMed

Drug Metab Dispos. 2022;50:770-780. Localization of xenobiotic transporters expressed at the human blood-estis barrier. Hau RK, Klein RR, Wright SH, Cherrington NJ. PubMed

Drug Metab Dispos. 2022;50:492-499. Strategies to diagnose Nonalcoholic Steatohepatitis: A novel approach to take advantage of pharmacokinetic alterations. Marie S, Tripp DKK, Cherrington NJ. PubMed

Mol Pharmacol. 2021;100:548-557. Remdesivir and EIDD-1931 interact with human Equilibrative Nucleoside Transporters 1 and 2: Implications for reaching SARS-CoV-2 viral sanctuary sites. Miller SR, McGrath ME, Zorn KM, Ekins S, Wright SH, Cherrington NJ. PubMed

Drug Metab Dispos. 2021;49:479-489. Multiple computational approaches for predicting drug interactions with human Equilibrative Nucleoside Transporter 1. Miller SR, Lane TR, Zorn KM, Ekins S, Wright SH, Cherrington NJ. PubMed

Toxicol Sci. 2021;181:1-2. Implications of species differences in function and localization of transporters at the blood-testis barrier. Hau RK, Miller SR, Cherrington NJ. PubMed

Mol Pharmacol. 2021;99:147-162. Predicting drug interactions with human Equilibrative Nucleoside Transporters 1 and 2 using functional Knockout cell lines and Bayesian modeling. Miller SR, Zhang X, Hau RK, Jilek JL, Jennings EQ, Galligan JJ, Foil DH, Zorn KM, Ekins S, Wright SH, Cherrington NJ. PubMed

Pharmaceutics. 2020;12:1005. 8. Generation of a hTERT-immortalized human Sertoli cell model to study transporter dynamics at the Blood-Testis Barrier. Hau RK, Miller SR, Wright SH, Cherrington NJ. PubMed

Drug Metab Dispos. 2020;48:603-612. Nucleoside Reverse Transcriptase Inhibitor (NRTI) interaction with human Equilibrative Nucleoside Transporters 1 and 2. Miller SR, Hau RK, Jilek JL, Morales MN, Wright SH, Cherrington NJ. PubMed

Biochem Pharmacol. 2020;174:113780. Interaction of Oatp1b2 expression and nonalcoholic steatohepatitis on pravastatin plasma clearance. Toth EL, Clarke JD, Csanaky IL, Cherrington NJ. PubMed

Toxicon. 2019;162:1-8. Nonalcoholic fatty liver disease alters microcystin-LR toxicokinetics and acute toxicity. Clarke JD, Dzierlenga A, Arman T, Toth E, Li H, Lynch KD, Tian DD, Goedken M, Paine MF, Cherrington N. PubMed

Toxicol Appl Pharmacol. 2019;368:49-54. Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis. Lake AD, Hardwick RN, Leamon CP, Low PS, Cherrington NJ. PubMed

Drug Metab Dispos. 2018;46:1478-1486. Gene-by-environment interaction of Bcrp-/- and Methionine- and Choline-Deficient Diet-induced Nonalcoholic Steatohepatitis alters SN-38 disposition. Toth EL, Li H, Dzierlenga AL, Clarke JD, Vildhede A, Goedken M, Cherrington NJ. PubMed

Toxicol Sci. 2018;164:428-438. Alcohol metabolism in the progression of human Nonalcoholic Steatohepatitis. Li H, Toth E, Cherrington NJ. PubMed

J Biochem Mol Toxicol. 2018;32:e22035. Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis. Dzierlenga AL, Cherrington NJ. PubMed

Toxicol Sci. 2018;161:23-33. Asking the right questions with animal models: Methionine- and choline-deficient model in predicting adverse Drug reactions in human NASH. Li H, Toth E, Cherrington NJ. PubMed

Oncotarget. 2017;8:63370-63381. Dysregulated expression of proteins associated with ER stress, autophagy and apoptosis in tissues from nonalcoholic fatty liver disease. Lee S, Kim S, Hwang S, Cherrington NJ, Ryu DY. PubMed

Drug Metab Dispos. 2017;45:1317-1325. Pediatric Cytochrome P450 activity alterations in Nonalcoholic Steatohepatitis. Li H, Mark CJ, Clarke JD, Billheimer D, Xanthakos SA, Lavine JE, Erickson RP, Cherrington NJ. PubMed

Liver Int. 2017;37:1074-1081. Impaired N-linked glycosylation of uptake and efflux transporters in human non-alcoholic fatty liver disease. Clarke JD, Novak P, Lake AD, Hardwick RN, Cherrington NJ. PubMed

Biochem Pharmacol. 2016;122:62-71. Transcription factor binding site enrichment analysis predicts drivers of altered gene expression in nonalcoholic steatohepatitis. Lake AD, Chaput AL, Novak P, Cherrington NJ, Smith CL. PubMed

J Biochem Mol Toxicol. 2017;31 (2). In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice. Li H, Clarke JD, Dzierlenga AL, Bear J, Goedken MJ, Cherrington NJ. PubMed

Drug Metab Dispos. 2016;44:1799-1807. Nonalcoholic Steatohepatitis modulates membrane protein retrieval and insertion processes. Dzierlenga AL, Clarke JD, Cherrington NJ. PubMed

Biochem Pharmacol. 2016;115:144-51. Effect of nonalcoholic steatohepatitis on renal filtration and secretion of adefovir. Laho T, Clarke JD, Dzierlenga AL, Li H, Klein DM, Goedken M, Micuda S, Cherrington NJ. PubMed

J Pharmacol Exp Ther. 2016;358:246-53. Biliary elimination of Pemetrexed is dependent on Mrp2 in rats: potential mechanism of variable response in Nonalcoholic Steatohepatitis. Dzierlenga AL, Clarke JD, Klein DM, Anumol T, Snyder SA, Li H, Cherrington NJ. PubMed

J Biochem Mol Toxicol. 2016;30:321-30. Altered hepatic transport by fetal arsenite exposure in diet-induced fatty liver disease. Ditzel EJ, Li H, Foy CE, Perrera AB, Parker P, Renquist BJ, Cherrington NJ, Camenisch TD. PubMed

Drug Metab Dispos. 2016;44:518-26. Hepatic transporter expression in metabolic syndrome: phenotype, serum metabolic hormones, and transcription factor expression. Donepudi AC, Cheng Q, Lu ZJ, Cherrington NJ, Slitt AL. PubMed

Diabetes. 2015;64:3305-13. Mechanism of altered Metformin distribution in nonalcoholic steatohepatitis. Clarke JD, Dzierlenga AL, Nelson NR, Li H, Werts S, Goedken MJ, Cherrington NJ. PubMed

Pharmacol Ther. 2015;151:99-106. Nonalcoholic steatohepatitis in precision medicine: unraveling the factors that contribute to individual variability. Clarke JD, Cherrington NJ. PubMed

Drug Metab Dispos. 2015;43:829-35.  Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis. Canet MJ, Merrell MD, Hardwick RN, Bataille AM, Campion SN, Ferreira DW, Xanthakos SA, Manautou JE, A-Kader HH, Erickson RP, Cherrington NJ. PubMed

J Pharmacol Exp Ther. 2015;352:462-70. Mechanistic basis of altered morphine disposition in nonalcoholic steatohepatitis. Dzierlenga AL, Clarke JD, Hargraves TL, Ainslie GR, Vanderah TW, Paine MF, Cherrington NJ. PubMed

Drug Metab Dispos. 2015;43:266-72. Renal xenobiotic transporter expression is altered in multiple experimental models of nonalcoholic steatohepatitis. Canet MJ, Hardwick RN, Lake AD, Dzierlenga AL, Clarke JD, Goedken MJ, Cherrington NJ. PubMed

Drug Metab Dispos. 2015;43:93-9. Identification of a functional antioxidant response element within the eighth intron of the human ABCC3 gene. Canet MJ, Merrell MD, Harder BG, Maher JM, Wu T, Lickteig AJ, Jackson JP, Zhang DD, Yamamoto M, Cherrington NJ. PubMed

Toxicol Sci. 2014;142:45-55. Increased susceptibility to methotrexate-induced toxicity in nonalcoholic steatohepatitis. Hardwick RN, Clarke JD, Lake AD, Canet MJ, Anumol T, Street SM, Merrell MD, Goedken MJ, Snyder SA, Cherrington NJ. PubMed

Expert Opin Drug Metab Toxicol. 2014;10:1209-19. Drug disposition alterations in liver disease: extrahepatic effects in cholestasis and nonalcoholic steatohepatitis. Canet MJ, Cherrington NJ. PubMed

J Hepatol. 2014;61:139-47. Synergistic interaction between genetics and disease on pravastatin disposition. Clarke JD, Hardwick RN, Lake AD, Lickteig AJ, Goedken MJ, Klaassen CD, Cherrington NJ. PubMed

J Pharmacol Exp Ther. 2014;348:452-8. Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression. Clarke JD, Hardwick RN, Lake AD, Canet MJ, Cherrington NJ. PubMed

Drug Metab Dispos. 2014;42:586-95.  Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models. Canet MJ, Hardwick RN, Lake AD, Dzierlenga AL, Clarke JD, Cherrington NJ. PubMed

Drug Metab Dispos. 2014;42:596-602. Selective and cytokine-dependent regulation of hepatic transporters and bile acid homeostasis during infectious colitis in mice. Merrell MD, Nyagode BA, Clarke JD, Cherrington NJ, Morgan ET. PubMed

Dig Dis Sci. 2014;59:365-74. Characterization of hepatocellular carcinoma related genes and metabolites in human nonalcoholic fatty liver disease. Clarke JD, Novak P, Lake AD, Shipkova P, Aranibar N, Robertson D, Severson PL, Reily MD, Futscher BW, Lehman-McKeeman LD, Cherrington NJ. PubMed

Drug Metab Dispos. 2013;41:1148-55. Alcohol cirrhosis alters nuclear receptor and drug transporter expression in human liver. More VR, Cheng Q, Donepudi AC, Buckley DB, Lu ZJ, Cherrington NJ, Slitt AL. PubMed

Drug Metab Dispos. 2013;41:554-61. Altered UDP-glucuronosyltransferase and sulfotransferase expression and function during progressive stages of human nonalcoholic fatty liver disease. Hardwick RN, Ferreira DW, More VR, Lake AD, Lu Z, Manautou JE, Slitt AL, Cherrington NJ. PubMed

Am J Physiol. 2013;304:G48-56. The hepatic bile acid transporters Ntcp and Mrp2 are downregulated in experimental necrotizing enterocolitis. Cherrington NJ, Estrada TE, Frisk HA, Canet MJ, Hardwick RN, Dvorak B, Lux K, Halpern MD. PubMed

Curr Protoc Toxicol. 2012;Chapter 23:Unit 23.1. Measuring altered disposition of xenobiotics in experimental models of liver disease. Hardwick RN, Cherrington NJ. PubMed

Expert Opin Drug Metab Toxicol. 2012;8:349-60. Genetics or environment in drug transport: the case of organic anion transporting polypeptides and adverse drug reactions. Clarke JD, Cherrington NJ. PubMed

Drug Metab Dispos. 2012;40:450-60. Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis. Hardwick RN, Fisher CD, Street SM, Canet MJ, Cherrington NJ. PubMed

Drug Metab Dispos. 2011;39:2395-402. Variations in ATP-binding cassette transporter regulation during the progression of human nonalcoholic fatty liver disease. Hardwick RN, Fisher CD, Canet MJ, Scheffer GL, Cherrington NJ. PubMed

Drug Metab Dispos. 2011;39:1954-60. Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease. Lake AD, Novak P, Fisher CD, Jackson JP, Hardwick RN, Billheimer DD, Klimecki WT, Cherrington NJ. PubMed

Drug Metab Rev. 2011;43:317-34. Drug metabolism alterations in nonalcoholic fatty liver disease. Merrell MD, Cherrington NJ. PubMed

Obesity (Silver Spring). 2017;25:1069-1076. Metabolomic profiling distinction of human nonalcoholic fatty liver disease progression from a common rat model. Han J, Dzierlenga AL, Lu Z, Billheimer DD, Torabzadeh E, Lake AD, Li H, Novak P, Shipkova P, Aranibar N, Robertson D, Reily MD, Lehman-McKeeman LD, Cherrington NJ. PubMed