The use of long-term hepatocyte cultures for detecting induction of drug metabolising enzymes: The current status - ECVAM hepatocytes and metabolically competent systems task force report 1

In this report, metabolically competent in vitro systems have been reviewed , in the context of drug metabolising enzyme induction. Based on the experi ence of the scientists involved, a thorough survey of the literature on met abolically competent long-term culture models was performed. Following this , a prevalidation proposal for the use of the collagen gel sandwich hepatoc yte culture system for drug metabolising enzyme induction was designed, foc using on the induction of the cytochrome P450 enzymes as the principal enzy mes of interest. The ultimate goal of this prevalidation proposal is to pro vide industry and academia with a metabolically competent in vitro alternat ive for long-term studies. In an initial phase, the prevalidation study wil l be limited to the investigation of induction. However, proposals for othe r long-term applications of these systems should be forwarded to the Europe an Centre for the Validation of Alternative Methods for consideration. The prevalidation proposal deals with several issues, including: a) species; b) practical prevalidation methodology; c) enzyme inducers; and d) advantages of working with independent expert laboratories. Since it is preferable to include other alternative tests for drug metabolising enzyme induction, wh en such tests arise, it is recommended that they meet the same level of dev elopment as for the collagen gel sandwich long-term hepatocyte system. Thos e tests which do so should begin the prevalidation and validation process.