Abstract
Accurately predicting hepatic clearance is an integral part of the drug-development process, and yet current in vitro to in vivo (IVIVE) extrapolation methods yield poor predictions, particularly for highly protein-bound transporter substrates. Explanations for error include inaccuracies in protein-binding measurements and the lack of recognition of protein-facilitated uptake, where both unbound and bound drug may be cleared, violating the principles of the widely accepted free drug theory. A new explanation for protein-facilitated uptake is proposed here, called a transporter-induced protein binding shift. High-affinity binding to cell-membrane proteins may change the equilibrium of the nonspecific binding between drugs and plasma proteins, leading to greater cellular uptake and clearance than currently predicted. The uptake of two lower protein-binding organic anion transporting polypeptide substrates (pravastatin and rosuvastatin) and two higher binding substrates (atorvastatin and pitavastatin) were measured in rat hepatocytes in incubations with protein-free buffer versus 100% plasma. Decreased unbound Km values and increased intrinsic clearance values were seen in the plasma incubations for the highly bound compounds, supporting the new hypothesis and mitigating the IVIVE underprediction previously seen for highly bound transporter substrates.
Footnotes
- Received December 11, 2018.
- Accepted January 18, 2019.
C.M.B. was supported in part by the Pharmaceutical Research and Manufacturers of America Foundation Predoctoral Fellowship in Pharmaceutics and the National Science Foundation Graduate Research Fellowship Program [Grant 1144247]; L.Z.B. is a member of the University of California San Francisco Liver Center and supported by the National Institutes of Health [Grant P30 DK026743].
- Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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