Inter-individual differences in the expression and activity of CYP3A4 in the mucosal epithelium of the small intestine contribute to a low and variable oral bioavailability that is observed for many drugs that are CYP3A substrates. This high degree of variability appears to be the result of large inter-individual differences in the specific content of CYP3A4 and CYP3A5 in human duodenal enterocytes. From a therapeutic perspective, large inter-patient differences in first-pass intestinal extraction efficiency can lead to differences in systemic exposure to the parent drug and its metabolites and pharmacological effects following oral administration of doses that are appropriate for the }average} patient, increasing the risk of therapeutic failure and adverse toxicity. The cause of variable intestinal CYP3A expression is largely unknown, but thought to involve both genetic and environmental/physiological factors. For example, we have shown previously that the most biologically active form of vitamin D, 1,25-(OH)2-vitamin D3, enhances transcription of the major drug metabolizing enzyme CYP3A4 in a VDR-dependent manner, and that CYP3A4 in turn can catalyze the metabolic clearance of 1,25- (OH)2-D3. The overall objectives of this grant proposal are to determine whether 1,25-(OH)2-D3 regulates the expression of CYP3A4 in the human small intestine in vivo, and whether the administration of drugs that affect CYP3A4 function through enzyme induction or inhibition alter the synthesis and function of intestinal calcium transport proteins through changes in 1,25-(OH)2-D3 disposition within the mucosal enterocyte. Specifically, we will test the hypothesis that 1,25-(OH)2-D3 enhances intestinal CYP3A4 expression and function by assessing the effects of oral 1,25-(OH)2-D3 administration on duodenal gene targets of the activated vitamin D receptor and CYP3A-dependent drug clearance. We will also test whether activation of CYP3A4 transcription provides auto-feedback control of VDR-mediated genomic effects by assessing the effects of CYP3A4 inhibitors and inducers on the responsiveness of human enterocytes to 1,25-(OH)2-D3. Finally, we will test whether activation of hPXR by known agonists enhances CYP3A4-dependent intestinal 1,25-(OH)2-D3 metabolism, resulting in a decrease in the transcription of intestinal VDR gene targets and a change in systemic indices of calcium homeostasis. Elucidating the molecular basis of inter-individual differences in CYP3A-dependent drug metabolism could enhance the ability of the drug industry to develop safe and efficacious drugs through a clearer understanding of how other medications, the environment, and disease states might impinge on the disposition of new drug candidates that are intestinal CYP3A substrates. In addition, if our hypothesis about the participation of CYP3A4 in negative feedback control of 1,25-(OH)2-D3 genomic effects within enterocytes of the small intestine proves to be correct, it could point to relatively simple ways (e.g., moderate daily grapefruit juice consumption) to prevent the adverse effects of potent hPXR agonists on bone health in }at-risk} patients. PROJECT NARRATIVE Completion of the specific aims proposed in this grant application should improve our understanding of the molecular basis for inter-individual differences in CYP3A4-dependent drug metabolism and potentially enhance the safety and efficacy of existing and new drugs used to treat disease. Moreover, it may provide a scientific basis for the effective prevention of some adverse drug effects that lead to osteoporosis. Public Health Relevance: Completion of the specific aims proposed in this grant application should improve our understanding of the molecular basis for inter-individual differences in CYP3A4-dependent drug metabolism and potentially enhance the safety and efficacy of existing and new drugs used to treat disease. Moreover, it may provide a scientific basis for the effective prevention of some adverse drug effects that lead to osteoporosis.
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