A new and simple method to test drug interactions with metabolic enzymes of rats in vivo.
The aim of this study was to develop a simple method for investigating drug influences on the cytochrome P-450 system of rats in vivo. The effects of diazepam on muscle coordination were quantified by the time the rats needed to descend a distance of 1 m on a rubberized bar hanging at an angle of 45 degrees. The effects of some previously identified inhibitors of the cytochrome P-450 system, e.g., SKF 525 A, metyrapone, ketoconazole, 2-phenylimidazole, nitrendipine, omeprazole and cimetidine, were tested and the 50% prolongation of diazepam effect was calculated. In order to stimulate the drug-metabolizing enzymes, pentobarbital was administered twice daily on three consecutive days. The running bar test constitutes a simple method to test for inhibition and induction of the cytochrome P-450 system by drugs. Because diazepam is often used as co-medication, the findings seem to be of greater clinical relevance than those obtained with other substrates. The newly developed test system can be used in addition to in vitro methods before clinical use of a drug and also as second screening test in the development of new drugs.
Hanauer
G
G
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, Germany.
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects*; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D010600:Pharmacology / Q000379:methods*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003975:Diazepam