Drug interactions are a major cause of adverse effects associated with drug polytherapy. The goal of this Program is to develop predictive models, based on a thorough understanding of interactions that are metabolically-linked, which can be used to reduce the incidence or severity of this serious therapeutic problem. The four projects proposed in this Program focus upon interactions which occur when several widely- used drugs (acetaminophen, carbamazepine, phenobarbital, phenytoin, valproic acid and warfarin) are components of polytherapy with enzyme activators, inducers and inhibitors. In Project 1, the ability to predict inhibitory interactions with a specific class of therapeutic agents - the anticonvulsants - using a pharmacokinetic model developed from prior studies with warfarin, will be examined. The hypothesis that an understanding of the P450 isoform(s) which catalyze the major pathways of anticonvulsant elimination, together with determination of an in vivo inhibition constant (Kiiv) is sufficient to predict the magnitude of any drug interaction that occurs as a consequence of inhibition of that isoform, will be tested. In Project 2 a computer-generated active-site model for a specific enzyme - P45029C9 - whose inhibition is the critical feature of many drug interactions involving warfarin will be constructed. This model will be based upon a knowledge of the pharmacophoric features which promote interaction of drugs with P45029C9 and its structural variants. The frequency of expression of allelic variants of P45029C9, their role in the modulation of warfarin biotransformation, and the impact of such a polymorphism on drug interactions with warfarin will also be assessed. Project 3 explores the biochemical mechanism behind a rare, but potentially fatal, hepatotoxicity associated with the use of valproic acid in polytherapy. These studies will test the hypothesis that valproate (and its reactive metabolites) act synergistically with co-administered anticonvulsants and an endogenous cytokine (tissue necrosis factor) to produce oxidative stress and liver damage. This project will examine aspects of the interplay between the metabolism of xenobiotics and endogenous lipids which have toxicological consequences. Project 4 will investigate the mechanism of interactions that occur with the analgesic/antipyretic agent acetaminophen, through alterations in production of its reactive metabolite in a target tissue, the liver. The inductive and inhibitory effects of isoniazid, and the activating effect of caffeine, will be examined at the molecular level in order to develop models that describe changes in acetaminophen oxidation in vivo. Modeling of the active site of those human P450 isoforms that oxidize acetaminophen (P450's 1A2, 2D1 and 3A3/4) will be conducted using NMR relaxation techniques, and the effect of omeprazole, a controversial inducer of P4501A2, on the oxidative metabolism of acetaminophen will be explored in this project. Collectively, the studies outlined in this proposal will extend our knowledge of the biochemical basis of clinically significant drug interactions, and will provide a theoretical framework upon which to predict such interactions.
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