The long-term goal of this project is to better understand drug-drug interactions that arise primarily from theinhibitory effects of drug metabolites, rather than from the effects of the drugs themselves. It is wellestablished that metabolites of drugs can be toxic, pharmacologically active, a cause of clinically significantdrug-drug interactions and/or the source of non-linear drug pharmacokinetics. Thus, metabolites often playan important role in therapeutics. Metabolite-based drug interactions that arise from the inhibitory effects ofdrug metabolites, rather than the parent drugs, on P450 enzyme activity are poorly understood and difficultto predict. Rationalization of these types of interaction requires simultaneous resolution of two of the majorscaling issues that plague drug metabolism research - (1) the application of in vitro data for a drug in orderto predict in vivo metabolite pharmacokinetics and (2) prediction of the magnitude of a drug-drug interactioncaused by a drug (in this case a metabolite) in vivo. The goal of this application is to establish theoreticallybasedand experimentally verified means to understand, detect and more reliably predict metabolicallybaseddrug interactions.
Aim 1 completes our in vivo and in vitro work on the stereoselective metabolism ofitraconazole (a potent inhibitor of drug metabolism in vivo) and the effects of the long lived, tight bindingmetabolites on enzyme activity and dose dependent pharmacokinetics of the parent drug.
Aim 2 focuses ona rationalization of the magnitude of drug-drug interactions that occur as the result of long term dosing offluoxetine with drugs that are cleared by CYP2D6, CYP2C19 and CYP3A4 and the role of fluoxetinemetabolites in these interactions. Experimental approaches use single recombinant enzymes, hepatocytesand in vivo interaction studies to test our predictions.
Aim 3 extends our work on the complexities of theirreversible inhibition of CYP3A4 by diltiazem and it's metabolites in single enzyme systems, microsomesand hepatocytes. The major objective here is to establish and rationalize new methods to meaningfullyquantify in vitro behavior when the inhibition is almost entirely driven by the concentrations of diltiazem'smetabolites. .Successful completion of these aims will provide powerful new tools to use in the prospectiveevaluation of metabolite-based drug interactions.
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