There is great interest and possible concern in the use of ethanol by HIV infected patients. Ethanol has been shown to induce cytochrome P450 (CYP) 3A, an isoform responsible for the metabolism of HIV PIs (HIV-PIs). The goal of this proposal is to evaluate the effects of ethanol consumption on the pharmacokinetics, specifically AUC and Cmax, of orally administered HIV-protease inhibitors. Two specific objectives are derived from this goal and are addressed in this application that will utilize two rodent models of ethanol consumption and its interaction on drug disposition.S.A.I: To characterize the pharmacokinetics of orally administered HIV protease inhibitors in rats fed the Leiber-DeCarli ethanol-containing diet, and pair fed and ad-lib controls. This model was chosen since it has been shown that ethanol can induce CYP3A without significant liver pathology and may be analogous to early alcohol disease. S.A.II: To characterize the pharmacokinetics of orally administered HIV protease inhibitors in rats fed ethanol and liquid diet via the intragastric tube feeding method. This model of ethanol consumption was chosen since it has been shown to be a better inducer of CYP3A and also cause substantial liver pathology.1) Characterize and compare the pharmacokinetics of select HIV protease inhibitors (HIV-PI) such as saquinavir and indinavir after their oral administration in these models (and controls) chronically fed ethanol. We will also ascertain the effects of pretreatment with triacetyloleandomycin (TAO), a specific inhibitor of CYP3A, on the pharmacokinetics of rally administered saquinavir and indinavir.2) Characterize and compare the pharmacokinetics of saquinavir and indinavir after oral co-administration with ethanol in these models.3) Validate the induction of CYP3A activity, content and specific inhibition of CYP3A by TAO in liver and small bowel in these rats. Since para-glycoprotein (pgp) can affect the bioavailability of HIV protease inhibitors we will also characterize the effects of chronic ethanol on pgp content.The success of antiretroviral medication therapies for the treatment of HIV-disease is now well documented. These benefits are only tenable when therapeutic levels of the antiviral treatments are maintained. Understanding drug interactions and induction of HIV-PI metabolism remains a critical goal for those individuals receiving treatment. Many individuals taking these medications also consume ethanol, acutely and chronically. Because of the importance of CYP3A4 with respect to HIV-PI drug metabolism, and its induction by ethanol, the interactions of HIV-PI and ethanol are of clinical importance and are the major focus of this proposal.
