COMPLICATIONS OF HIV DISEASE AGENDA

这项提案将检验艾滋病毒阳性者减少的假设， 通过肝细胞色素P450酶代谢药物的能力，以及 这种减少是继发于增强的抗病毒免疫力。 这 提出这一假设是因为动物和人类研究都 证明了免疫和免疫功能之间存在负相关性， 药物通过肝细胞色素的刺激和氧化代谢 P450酶。 由于慢性艾滋病毒感染与免疫相关， 激活表现为血清干扰素、TNF-α升高， 尿新喋呤，很可能是艾滋病毒+的人有扰动 肝脏细胞色素P450酶的活性 由于艾滋病毒阳性者被规定 许多由肝P450酶代谢的药物（例如， 苯二氮卓类，抗抑郁药，麻醉性镇痛药，以及一些新的 抗逆转录病毒药物），这些药物代谢的任何扰动 在达到治疗效果方面具有深远的影响， 避免毒性。 我们建议研究三种原型药物的代谢 （咖啡因，茶碱，利多卡因）在50 - 60个HIV+个体中， 阶段的艾滋病毒感染，和20个正常的，年龄匹配的艾滋病毒对照。 咖啡因 将口服给药，5种尿代谢物浓度将 使用HPLC和UV检测技术进行估计。 通过建立 这些代谢物的尿液浓度的特定比例，4 可以评估不同的酶途径，两种细胞色素P450酶 （7-去甲基化途径和8-羟基化途径），黄嘌呤氧化酶， 和N-乙酰基转移酶。 由于黄嘌呤氧化酶的刺激已经 推测是P450酶活性降低的原因 干扰素给药后，咖啡因代谢物的比例将是 非常有启发性。 尿液采集无法评估重要性 药代动力学参数如清除率和分布容积。 因此，茶碱和利多卡因将用于实现这一点。 利多卡因是一种高肝清除率药物， 细胞色素P450酶 茶碱将静脉注射， 频繁的血浆浓度监测和VD和肝脏清除率将 使用标准药代动力学公式计算。 利多卡因会 口服和静脉注射同时进行。 口服利多卡因 在代谢惰性位置上有两个氘原子。 血液 将测定标记和未标记利多卡因的浓度 使用GC-MS技术。 全身肝清除率，固有肝清除率 清除率、VD和肝血流量将使用标准 公式。 干扰素-α，干扰素-γ， 肿瘤坏死因子-α和新蝶呤的排泄率 在口服咖啡因测试之前收集的。 代谢率和肝脏 将在HIV+和HIV-受试者之间比较这些药物的清除率。 此外，将使用回归分析将这些 代谢参数到抗病毒状态激活的水平。 这些 数据应确定艾滋病毒感染在多大程度上损害肝脏 三种原型药物的细胞色素P450代谢。 之结果 数据可以改善艾滋病毒药物的合理使用 被感染的对象

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.