Altered Hepatic Disposition of Statins by Diabetes Mellitus

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DESCRIPTION (provided by applicant): Drug metabolizing enzymes (DMEs) and transporters mediate detoxification and elimination of a wide range of compounds, although minimal data are available on the regulation and activity of these mechanisms in humans with type 1 or type 2 diabetes mellitus. Recently, we have observed significantly higher concentrations of atorvastatin (ATV) lactones in patients with diabetes mellitus. Furthermore, in the livers of diabetic donors, we have shown significant downregulation of cytochrome P450 3A4 (CYP3A4) that is responsible for the biotransformation of approximately 55% of all marketed medications. This observation may explain, in part, our clinical observations of a reduced clearance of ATV in diabetic patients. The broad long-term objective of this project is to improve pharmacotherapy in patients with diabetes mellitus. The objective of the current proposal, in the context of a R15 grant mechanism, is to characterize the effect of diabetes type (type 1 vs. type 2) on the expression and activity of DMEs and transport mechanisms responsible for disposition of ATV. The central hypothesis is that diabetes and associated conditions differentially regulate DMEs and transport mechanisms, thus, resulting in the altered clearance of xenobiotics including ATV. The rationale for this study is that understanding the effect of diabetes on DME or transport mechanisms will assist clinicians to make more-informed choices for the treatment of individual patients. The specific aims are to (1) Characterize the effect of diabetes type and degree of hyperglycemia and/or fatty liver on the CYP3A4 activity and regulation using human livers from type 1 vs. type 2 diabetic and non-diabetic donors (2) Evaluate the contribution of non-CYP3A4 factors on hepatic disposition of ATV and (3) Describe the inter-play between different factors associated with diabetes on the regulation of drug metabolizing enzymes and transporters, by the use of primary human hepatocyte cultures. Collectively, the studies described in this proposal should provide useful information on the effect of diabetes mellitus on ATV metabolism and transport. An understanding of the effects of diabetes on the mechanisms governing ATV disposition may help in devising safer and more efficacious dosing methods for statins in this patient group. PUBLIC HEALTH RELEVANCE: Epidemiological studies suggest that statin cholesterol lowering agents, generate more side effects in patients with diabetes mellitus. Diabetes is likely to influence several mechanisms governing drug disposition, including changes in the activity of enzymes that break down drug molecules. Our aim is to characterize the effects of diabetes on several mechanisms responsible for the clearance of statins from the human body.