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.
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