Clearance Prediction of Targeted Covalent Inhibitors by In Vitro-In Vivo Extrapolation of Hepatic and Extrahepatic Clearance Mechanisms.

Autor:	Leung L; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.)., Yang X; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.)., Strelevitz TJ; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.)., Montgomery J; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.)., Brown MF; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.)., Zientek MA; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.)., Banfield C; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.)., Gilbert AM; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.)., Thorarensen A; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.)., Dowty ME; Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.) martin.dowty@pfizer.com.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2017 Jan; Vol. 45 (1), pp. 1-7. Date of Electronic Publication: 2016 Oct 26.
DOI:	10.1124/dmd.116.072983
Abstrakt:	The concept of target-specific covalent enzyme inhibitors appears attractive from both an efficacy and a selectivity viewpoint considering the potential for enhanced biochemical efficiency associated with an irreversible mechanism. Aside from potential safety concerns, clearance prediction of covalent inhibitors represents a unique challenge due to the inclusion of nontraditional metabolic pathways of direct conjugation with glutathione (GSH) or via GSH S-transferase-mediated processes. In this article, a novel pharmacokinetic algorithm was developed using a series of Pfizer kinase selective acrylamide covalent inhibitors based on their in vitro-in vivo extrapolation of systemic clearance in rats. The algorithm encompasses the use of hepatocytes as an in vitro model for hepatic clearance due to oxidative metabolism and GSH conjugation, and the use of whole blood as an in vitro surrogate for GSH conjugation in extrahepatic tissues. Initial evaluations with clinical covalent inhibitors suggested that the scaling algorithm developed from rats may also be useful for human clearance prediction when species-specific parameters, such as hepatocyte and blood stability and blood binding, were considered. With careful consideration of clearance mechanisms, the described in vitro-in vivo extrapolation approach may be useful to facilitate candidate optimization, selection, and prediction of human pharmacokinetic clearance during the discovery and development of targeted covalent inhibitors. (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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