The human immunodeficiency viral protease inhibitors (HIV PIs), as a component of multiple drug therapy with other Highly Active Anti- Retroviral Therapies (HAART), have profoundly changed the prognosis and quality of life for individuals with HIV infection. Nonetheless PIs and other HAART drugs are not curative of HIV, and resurgence of viral load (possibly with resistant forms) from viral reservoirs (""""""""breakthrough"""""""") remains a clinical problem of ongoing concern. Pharmacokinetic variability - - particularly that leading to periods of low or undetectable levels of one or more HAART drugs - - may predispose to breakthrough and resistance. One major source of variability derives from the relation of the kinetics of HAART drugs to the human Cytochrome P450-3A (CYP3A) isoforms, which mediate the metabolism of the HAART drugs themselves and many other compounds, and to P- glycoprotein (P-gp), a transport protein localized in GI tract mucosa and the blood-brain barrier. Many of the important HAART drugs are inhibitors and/or inducers of CYP3A and/or of P-gp, producing complex and time-dependent interactions involving their own metabolism (i.e.,autoinduction) as well as interactions with other coadministered classes of medications. Dysregulation of CYP3A by HIV PIs, and possibly other HAART components, has been linked to metabolic consequences of HIV such as lipodystrophy, insulin resistance, and hyperlipidemia. The present proposal utilizes related clinical and molecular techniques to provide definitive data on the extent, time course, and consequences of the interaction of HAART components with CYP3A and P-gp, using the PI ritonavir as the index compound. A. In clinical studies, midazolam (given I.V. and orally) is used as a probe CYP3A substrate to determine the effects of ritonavir on hepatic and gastrointestinal CYP3A function under the following conditions: control, prior to ritonavir exposure; with acute ritonavir exposure (inhibition); during extended ritonavir exposure (combined induction and inhibition); following extended ritonavir exposure (induction only). Parallel studies of P-gp regulation are performed using fexofenadine as the index substrate. B. A human adenocarcinoma cell culture model will evaluate the time-course and concentration-dependence of P-gp upregulation by HAART drugs, based on immunoquantitative techniques as well as functional assays of P-gp dependent cell exclusion of a fluorescent probe. This multidisciplinary proposal provides a clinical and scientific basis to assess the effects of currently available as well as experimental HAART medications on human CYP3A and P-gp.
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