A COMMENTARY ON THE USE OF HEPATOCYTES IN DRUG METABOLISM STUDIES DURING DRUG DISCOVERY AND DEVELOPMENT*

Abstract

Isolated hepatocytes and liver slices, in short-term suspension or longer-term culture, offer the prospect of providing qualitative metabolic information and quantitative pharmacokinetic parameters from key animal species and man at early stages of the drug discovery–development continuum. The propensity for changes in the fidelity of drug metabolism after removal of hepatocytes from the organ has long been recognized. The many and varied approaches which have been undertaken in an attempt to compensate for physiological shortcomings of in vitro hepatocyte systems are reviewed. In this respect, short-term suspension culture may provide a baseline against which to measure the success of extended culture methods, but it should be remembered that even freshly isolated hepatocyte preparations have deficiencies and liabilities that may affect the nature of information gathered. This article discusses the current advances and shortcomings of hepatocyte suspensions and cultures, along with liver slice technology, at both quantitative and qualitative levels.

Key Words :

• Hepatocytes
• Liver slices
• Cell culture
• Cryopreservation
• Drug metabolism
• Enzyme kinetics
• Ranitidine
• Loxtidine
• Intrinsic clearance
• Hepatic clearance
• Extraction ratio

Notes

This paper was refereed by Dr. Jan G. Hengstler, Institute of Toxicology, University of Mainz, Germany.