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J Pharm Sci. 2019 Apr 30. pii: S0022-3549(19)30252-7. doi: 10.1016/j.xphs.2019.04.019. [Epub ahead of print]

Preincubation With Everolimus and Sirolimus Reduces Organic Anion-Transporting Polypeptide (OATP)1B1- and 1B3-Mediated Transport Independently of mTOR Kinase Inhibition: Implication in Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interactions.

Author information

1
Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
2
Certara UK Ltd., Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, UK.
3
Yale MS & Proteomics Resource, Yale University, New Haven, Connecticut.
4
Yale MS & Proteomics Resource, Yale University, New Haven, Connecticut; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut.
5
Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
6
Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: wei-yue@ouhsc.edu.

Abstract

Organic anion transporting polypeptides (OATP)1B1 and OATP1B3 mediate hepatic uptake of many drugs including lipid-lowering statins. Current studies determined the OATP1B1/1B3-mediated drug-drug interaction (DDI) potential of mammalian target of rapamycin (mTOR) inhibitors, everolimus and sirolimus, using R-value and physiologically based pharmacokinetic models. Preincubation with everolimus and sirolimus significantly decreased OATP1B1/1B3-mediated transport even after washing and decreased inhibition constant values up to 8.3- and 2.9-fold for OATP1B1 and both 2.7-fold for OATP1B3, respectively. R-values of everolimus, but not sirolimus, were greater than the FDA-recommended cutoff value of 1.1. Physiologically based pharmacokinetic models predict that everolimus and sirolimus have low OATP1B1/1B3-mediated DDI potential against pravastatin. OATP1B1/1B3-mediated transport was not affected by preincubation with INK-128 (10 μM, 1 h), which does however abolish mTOR kinase activity. The preincubation effects of everolimus and sirolimus on OATP1B1/1B3-mediated transport were similar in cells before preincubation with vehicle control or INK-128, suggesting that inhibition of mTOR activity is not a prerequisite for the preincubation effects observed for everolimus and sirolimus. Nine potential phosphorylation sites of OATP1B1 were identified by phosphoproteomics; none of these are the predicted mTOR phosphorylation sites. We report the everolimus/sirolimus-preincubation-induced inhibitory effects on OATP1B1/1B3 and relatively low OATP1B1/1B3-mediated DDI potential of everolimus and sirolimus.

KEYWORDS:

drug interactions; drug transport; hepatic transport; hepatocytes; organic anion-transporting polypeptide; pharmacokinetics; phosphorylation; physiologically based pharmacokinetic modeling; post-translational modification; transporters

PMID:
31047942
DOI:
10.1016/j.xphs.2019.04.019

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