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.

Keywords:

• Mouse
• rat
• clearance
• protein binding
• intrinsic clearance
• lead optimization

Acknowledgements

The authors wish to thank Diane Talaber Kepner, Xinhe Jiang, Hong Cao, Rocco DelConte, and Logan Umberger for expert technical assistance; and GSK Drug Discovery scientists who synthesized and characterized the biological properties of the lead molecules herein described.