Physiologically based pharmacokinetics modeling and transporter proteomics to predict systemic and local liver and muscle disposition of statins.

Publisher: Wiley Country of Publication: United States NLM ID: 101580011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2163-8306 (Electronic) Linking ISSN: 21638306 NLM ISO Abbreviation: CPT Pharmacometrics Syst Pharmacol Subsets: MEDLINE

Publication: 2015- : Hoboken, NJ : Wiley
Original Publication: New York, NY : Nature Pub. Group

Hydroxymethylglutaryl-CoA Reductase Inhibitors*/pharmacokinetics ; Liver*/metabolism ; Proteomics*/methods ; Models, Biological* ; Organic Anion Transporters*/metabolism; Humans ; Muscle, Skeletal/metabolism ; Multidrug Resistance-Associated Proteins/metabolism ; Drug Interactions ; Tissue Distribution ; Male

Statins are used to reduce liver cholesterol levels but also carry a dose-related risk of skeletal muscle toxicity. Concentrations of statins in plasma are often used to assess efficacy and safety, but because statins are substrates of membrane transporters that are present in diverse tissues, local differences in intracellular tissue concentrations cannot be ruled out. Thus, plasma concentration may not be an adequate indicator of efficacy and toxicity. To bridge this gap, we used physiologically based pharmacokinetic (PBPK) modeling to predict intracellular concentrations of statins. Quantitative data on transporter clearance were scaled from in vitro to in vivo conditions by integrating targeted proteomics and transporter kinetics data. The developed PBPK models, informed by proteomics, suggested that organic anion-transporting polypeptide 2B1 (OATP2B1) and multidrug resistance-associated protein 1 (MRP1) play a pivotal role in the distribution of statins in muscle. Using these PBPK models, we were able to predict the impact of alterations in transporter function due to genotype or drug-drug interactions on statin systemic concentrations and exposure in liver and muscle. These results underscore the potential of proteomics-guided PBPK modeling to scale transporter clearance from in vitro data to real-world implications. It is important to evaluate the role of drug transporters when predicting tissue exposure associated with on- and off-target effects.
(© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
0 (Organic Anion Transporters)
0 (SLCO2B1 protein, human)
0 (Multidrug Resistance-Associated Proteins)

Date Created: 20240405 Date Completed: 20240615 Latest Revision: 20240618

20240618

PMC11179708

10.1002/psp4.13139

38576225