This proposal will test the hypotheses that HIV+ people have decreased ability to metabolize drugs via the hepatic cytochrome P450 enzymes, and that this decrease is secondary to enhanced antiviral immunity. This hypothesis is put forth because both animal and human studies have demonstrated that there is an inverse correlation between immune stimulation and oxidative metabolism of drugs via the hepatic cytochrome P450 enzymes. Since chronic HIV infection is associated with immune activation manifested by elevations of serum interferons, TNF-alpha, and urinary neopterin, it is quite likely that HIV+ people have perturbations in the hepatic cytochrome P450 enzymes. Since HIV+ people are prescribed numerous drugs that are metabolized by the liver P450 enzymes (e.g., benzodiazepines, antidepressants, narcotic analgesics, and some of the new anti-retroviral drugs), any perturbation in the metabolism of these drugs has far-reaching implications in terms of achieving therapeutic efficacy and avoiding toxicity. We are proposing to study the metabolism of three prototype drugs (caffeine, theophylline, lidocaine) in 50-60 HIV+ individuals at varying stages of HIV infection, and 20 normal, age-matched HIV-controls. Caffeine will be administered orally, and 5 urinary metabolite concentrations will be estimated using HPLC with UV detection technology. By setting up specific ratios of urinary concentrations of these metabolites, four different enzymatic pathways can be evaluated, two cytochrome P450 enzymes (7-demethylation pathway, and 8-hydroxylation pathway), xanthine oxidase, and N-acetyl transferase. Since stimulation of xanthine oxidase has been proposed to be responsible for the decrease in P450 enzymatic activity after interferon administration, the caffeine metabolite ratios will be very informative. Urinary collection cannot evaluate important pharmacokinetic parameters like clearance and volume of distribution. Therefore, theophylline and lidocaine will be used to accomplish that. Lidocaine is a high hepatic clearance drug that is metabolized by cytochrome P450 enzyme. Theophylline will be given intravenously with frequent plasma concentration monitoring and VD and hepatic clearance will be calculated using standard pharmacokinetic formulas. Lidocaine will be administered orally and intravenously at the same time. Oral lidocaine will have 2 deuterium atoms at a metabolically inert position. Blood concentrations of both labelled and unlabelled lidocaine will be determined using GC-MS technology. systemic hepatic clearance, intrinsic hepatic clearance, VD, and liver blood flow will be estimated using standard formulas. Serum concentrations of interferon-alpha, interferon-gamma, tumor necrosis factor-alpha, and neopterin excretion rates will be collected before the oral caffeine test. Metabolic ratios and hepatic clearances of these drugs will be compared between HIV+ and HIV- subjects. In addition, a regression analysis will be used to correlate these metabolic parameters to the level of antiviral state activation. These data should determine to what degree HIV infection impairs hepatic cytochrome P450 metabolism of three prototype drugs. The findings of these data can improve the rational use of a whole host of drugs used in HIV infected subjects.
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