Strain-Dependent Variability of Early Discovery Small Molecule Pharmacokinetics in Mice: Does Strain Matter?

Autor: Barr JT; Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California., Tran TB; Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California., Rock BM; Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California., Wahlstrom JL; Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California., Dahal UP; Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California udahal@amgen.com.
Jazyk: angličtina
Zdroj: Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2020 Aug; Vol. 48 (8), pp. 613-621. Date of Electronic Publication: 2020 May 30.
DOI: 10.1124/dmd.120.090621
Abstrakt: Drug discovery programs routinely perform pharmacokinetic (PK) studies in mice to prioritize lead compounds based on anticipated exposure-efficacy and exposure-toxicity relationships. Because of logistical and/or technical issues, the strain of mouse in early discovery PK studies may not always match the strain in toxicity or efficacy studies. This elicits the question do appreciable strain-dependent differences in PK parameters exist to an extent that would warrant conducting PK studies in a strain that matches efficacy and toxicity models? To understand the impact that strain may have on PK parameters, we selected eight marketed drugs with well characterized absorption, distribution, metabolism, and excretion properties and diverse structures to perform PK studies in three common mouse strains (Bagg Albino c, C57BL/6, and CD-1). Some statistical strain-dependent differences were observed; however, we found good general agreement of PK parameters between strains: 88%, 100%, 75%, 76%, 94%, and 88% of compounds were within twofold across strains for clearance, volume of distribution at steady state, t 1/2 , C max , T max , and oral bioavailability, respectively. Overall, we recommend that an approach using a single strain of mouse is appropriate for discovery screening PK studies, provided that proper caution is exercised. SIGNIFICANCE STATEMENT: The mouse strain in discovery pharmacokinetic (PK) studies may not match the strain in efficacy and toxicology studies. Currently, there is a gap in the literature addressing whether differences in PK parameters across mouse strains exist such that multiple PK studies are warranted. The results from this study indicated that the PK properties of clinically used drugs between mouse strains are within an acceptable range such that single strain PK is appropriate.
(Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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