Quantitative Proteomics and Mechanistic Modeling of Transporter‐Mediated Disposition in Nonalcoholic Fatty Liver Disease

Clinical Pharmacology and Therapeutics - Tập 107 Số 5 - Trang 1128-1137 - 2020
Anna Vildhede1, Emi Kimoto1, Ryan M. Pelis2, A. David Rodrigues1, Manthena V. S. Varma1
1Medicine Design, Worldwide R&D, Pfizer Inc., Groton, Connecticut, USA
2Department of Pharmaceutical Sciences, Binghamton University, Binghamton, New York, USA

Tóm tắt

Understanding transporter‐mediated drug disposition and pharmacokinetics (PK) in patients with nonalcoholic fatty liver disease (NAFLD) is critical in developing treatment options. Here, we quantified the expression levels of major drug transporters in healthy, steatosis, and nonalcoholic 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. Physiologically‐based pharmacokinetic 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), 99mTC‐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.

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Clinical Pharmacology and Therapeutics

Tập 107 Số 5

1128-1137

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