Differences in the total body clearance of lead compounds in the rat and mouse: Impact on pharmacokinetic screening strategy

Abstract

1. The in vivo clearance (CL) for 498 compounds representing more than 40 lead optimization programmes were compared in the rat and mouse.2. A total of 278 of the compounds had similar CL values in rat and mouse and 41 compounds had a high CL in one rodent species and a low CL in the other (median seven-fold difference). For this latter subset, comparative in vitro plasma protein binding, liver microsomal or hepatocyte intrinsic CL provided plausible explanations for the observed in vivo differences in many cases.3. A considerable proportion of compounds with substantially different CL in rodents, and those with a high CL in both rat and mouse, had a low-to-moderate CL in dog and/or monkey (43%). A larger proportion (71%) had promising pharmacokinetics in higher species when CL was low in both rat and mouse.4. Drug-discovery scientists should consider the potential for there to be substantial differences in the disposition of leads in different rodent species and design screening cascades to explore this possibility.