DELIVERY OF ANTI-AIDS DRUG 2-3 DIDEOXYINOSINE

2‘，3’-二脱氧肌苷(DdIno)对人类免疫缺陷有效 病毒(HIV)在体外。它目前处于I期临床试验。这个 HIV感染的慢性化需要持续的治疗以维持 有效抑制药物在血浆和脑脊液中的浓度 流体。需要药代动力学数据来确定给药剂量 会产生治疗性和无毒性的药物浓度 在血液和脑脊液中。然而，有有限的 在ddIno上的药代动力学数据。在少数接受口服治疗的患者中 剂量方面，ddIno的系统生物利用度在6%至50%之间。这 较大的学科间差异可能会产生不同的药理作用 对患者的影响和反应。低生物利用度表明 超过50%的剂量在到达全身之前就丢失了 发行量。造成这种剂量大范围损失的原因是 到达体循环还是个未知数。损失可能是由于 胃肠道和肝脏的发作期前代谢 胃的不完全吸收和/或降解。 我们研究计划的长期目标是改善 DdIno的生物利用度和全身给药。增加了 统一的生物利用度将减少受试者之间的可变性和 增强毒品活性。眼前的目标是描述 DdIno的药代动力学、口服给药后的药动学及药动学研究 其口服生物利用度低且多变的原因及探讨 不同的非肠外给药途径。这些数据将有助于 了解ddIno的吸收、分布和代谢，并 确定更好地给药的策略。DdIno可用于 与另一种有效的抗艾滋病毒化合物3‘-叠氮- 3‘脱氧胸腺嘧啶核苷(AZT)，它能竞争吸收和 DdIno的代谢。我们将检查潜在的药代动力学 DdIno和AZT之间的相互作用。老鼠将被用于这些研究。

2',3'-Dideoxyinosine (ddIno) is effective against human immunodeficiency virus (HIV) in vitro. It is currently in Phase I clinical trials. The chronicity of HIV infection requires continuous therapy to maintain an effective inhibitory drug concentration in plasma and cerebrospinal fluid. Pharmacokinetic data are needed to ascertain that the doses given to patients will produce the therapeutic and nontoxic drug concentrations in blood and cerebrospinal fluid. However, there are limited pharmacokinetic data on ddIno. IN the few patients who received oral doses, ddIno has a systemic bioavailability of between 6 to 50%. This large intersubject variation is likely to produce different pharmacologic effects and responses in patients. The low bioavailability indicates that more than 50% of the dose is lost prior to reaching the systemic circulation. The cause of this extensive loss of the dose prior to reaching the systemic circulation is unknown. The loss could be due to presystemic metabolism in the gastrointestinal tract and liver, incomplete absorption and/or degradation in the stomach. The long range goal of our research plan is to improve the bioavailability and systemic delivery of ddIno. An increased bioavailability towards unity will reduce intersubject variability and enhance drug activity. The immediate objectives are to characterize the pharmacokinetics of ddIno, its disposition after oral administration and the cause of its low and variable oral bioavailability, and to explore different nonparenteral administration routes. These data will help to understand the absorption, distribution and metabolism of ddIno, and to define strategies for a better drug delivery. ddIno may be used in combination with another potent anti-HIV compound, 3'-azido- 3'deoxythymidine (AZT), which can compete for the absorption and metabolism of ddIno. We will examine potential pharmacokinetic interactions between ddIno and AZT. Rats will be used for these studies.