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THE USE OF A SUBSTRATE CASSETTE STRATEGY TO IMPROVE THE CAPACITY AND THROUGHPUT OF CYTOCHROME P450 INDUCTION STUDIES IN HUMAN HEPATOCYTES

Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana

The gold standard for estimating the ability of a new chemical entity to induce the human cytochromes P450 (P450s) is to determine the increase in catalytic activity of these enzymes after treatment of primary cultures of human hepatocytes with the potential inducer. The limited availability of fresh human hepatocytes makes these studies impossible to perform on demand. A substrate cassette strategy in which probe substrates for three different P450s were simultaneously added to hepatocyte preparations was studied to determine whether this would be a viable method to increase the capacity of induction studies. The biotransformations of phenacetin (CYP1A2), diclofenac (CYP2C9), and midazolam (CYP3A) were compared when administered to four different hepatocyte preparations (±inducer) individually or simultaneously as a cassette. The determinations of fold-induction in response to known inducers were not significantly affected, although slight differences were occasionally observed between the various P450 activities, whether determined individually or in the cassette. In total, for three P450 activities in the four hepatocyte preparations with and without inducer, no trend demonstrating a drug-drug interaction among any of the three probes was detected. The lack of interactions between the probe substrates demonstrates that this cassette strategy may be used in primary human hepatocyte induction studies without concern that the interactions between the substrates may be affecting the results, as has been seen in other cassette dosing experiments. Therefore, this substrate cassette is an excellent method for increasing the capacity and throughput of human hepatocyte induction studies by combining three experiments into one.

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