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Quantitative Proteomics and Mechanistic Modeling of Transporter-mediated Disposition in Non-Alcoholic Fatty Liver Disease.

Abstract

Understanding transporter-mediated drug disposition and pharmacokinetics (PK) in patients with non-alcoholic fatty liver disease (NAFLD) is critical in developing treatment options. Here, we quantified the expression levels of major drug transporters in healthy, steatosis and non-alcoholic steatohepatitis (NASH) liver samples, via liquid-chromatography tandem mass spectrometry-based proteomics, and used the data to predict the PK of substrate drugs in the disease state. Expression of organic anion transporting polypeptides (OATPs) and multidrug resistance-associated protein (MRP)2 is significantly lower in NASH livers; whereas, MRP3 is induced while no change was observed for organic cation transporter (OCT)1. PBPK models verified with PK data from healthy subjects well recovered the PK in NASH subjects for morphine (involving OCT1) and its glucuronide metabolites (MRP2/MRP3/OATP1B), 99m TC-mebrofenen (OATP1B/MRP2/MRP3), and rosuvastatin (OATP1B/breast cancer resistance protein). Overall, considerations to altered protein expression can enable quantitative prediction of PK changes in subjects with NAFLD.

Authors+Show Affiliations

Medicine Design, Worldwide R&D, Pfizer Inc, Groton, CT.Medicine Design, Worldwide R&D, Pfizer Inc, Groton, CT.Department of Pharmaceutical Sciences, Binghamton University, Binghamton, NY.Medicine Design, Worldwide R&D, Pfizer Inc, Groton, CT.Medicine Design, Worldwide R&D, Pfizer Inc, Groton, CT.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31630405

Citation

Vildhede, Anna, et al. "Quantitative Proteomics and Mechanistic Modeling of Transporter-mediated Disposition in Non-Alcoholic Fatty Liver Disease." Clinical Pharmacology and Therapeutics, 2019.
Vildhede A, Kimoto E, Pelis RM, et al. Quantitative Proteomics and Mechanistic Modeling of Transporter-mediated Disposition in Non-Alcoholic Fatty Liver Disease. Clin Pharmacol Ther. 2019.
Vildhede, A., Kimoto, E., Pelis, R. M., Rodrigues, A. D., & Varma, M. V. S. (2019). Quantitative Proteomics and Mechanistic Modeling of Transporter-mediated Disposition in Non-Alcoholic Fatty Liver Disease. Clinical Pharmacology and Therapeutics, doi:10.1002/cpt.1699.
Vildhede A, et al. Quantitative Proteomics and Mechanistic Modeling of Transporter-mediated Disposition in Non-Alcoholic Fatty Liver Disease. Clin Pharmacol Ther. 2019 Oct 20; PubMed PMID: 31630405.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quantitative Proteomics and Mechanistic Modeling of Transporter-mediated Disposition in Non-Alcoholic Fatty Liver Disease. AU - Vildhede,Anna, AU - Kimoto,Emi, AU - Pelis,Ryan M, AU - Rodrigues,A David, AU - Varma,Manthena V S, Y1 - 2019/10/20/ PY - 2019/10/21/entrez PY - 2019/10/21/pubmed PY - 2019/10/21/medline KW - non-alcoholic steatohepatitis KW - physiologically-based pharmacokinetic model KW - quantitative proteomics KW - transporter expression JF - Clinical pharmacology and therapeutics JO - Clin. Pharmacol. Ther. N2 - Understanding transporter-mediated drug disposition and pharmacokinetics (PK) in patients with non-alcoholic fatty liver disease (NAFLD) is critical in developing treatment options. Here, we quantified the expression levels of major drug transporters in healthy, steatosis and non-alcoholic steatohepatitis (NASH) liver samples, via liquid-chromatography tandem mass spectrometry-based proteomics, and used the data to predict the PK of substrate drugs in the disease state. Expression of organic anion transporting polypeptides (OATPs) and multidrug resistance-associated protein (MRP)2 is significantly lower in NASH livers; whereas, MRP3 is induced while no change was observed for organic cation transporter (OCT)1. PBPK models verified with PK data from healthy subjects well recovered the PK in NASH subjects for morphine (involving OCT1) and its glucuronide metabolites (MRP2/MRP3/OATP1B), 99m TC-mebrofenen (OATP1B/MRP2/MRP3), and rosuvastatin (OATP1B/breast cancer resistance protein). Overall, considerations to altered protein expression can enable quantitative prediction of PK changes in subjects with NAFLD. SN - 1532-6535 UR - https://www.unboundmedicine.com/medline/citation/31630405/Quantitative_Proteomics_and_Mechanistic_Modeling_of_Transporter-mediated_Disposition_in_Non-Alcoholic_Fatty_Liver_Disease L2 - https://doi.org/10.1002/cpt.1699 DB - PRIME DP - Unbound Medicine ER -