PHARMACOKINETICS OF AN ANTISENSE PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE AGAINST REV FROM HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IN THE ADULT MALE-RAT FOLLOWING SINGLE INJECTIONS AND CONTINUOUS-INFUSION

An antisense phosphorothioate oligodeoxynucleotide 27-mer complementar y to the rev gene mRNA of the human immunodeficiency virus (HIV-1) was administered to rats through intravenous injections and subcutaneous infusions in order to investigate the disposition of this compound. In addition, nonlethal toxic responses of the rat were evaluated. A biph asic plasma clearance with t1/2alpha of 20-25 min and t1/2beta of 27-4 1 hr was observed. Single doses ranging from 35 to 3257 mug were exami ned, and the plasma concentration and area under the plasma concentrat ion-time curve (AUC) were found to be directly proportional to the dos e. Continuous subcutaneous infusion of 50 mg over 28 days was also exa mined. The oligonucleotide is completely eliminated in the urine over 3 days. Electrophoretic analysis demonstrated that the excreted compou nd has the same mobility and UV-absorbance profile as the administered compound. Measurement of accumulation and distribution into tissues r evealed unique tissue-specific rates and extent of oligonucleotide mov ement into and out of tissues. Results of the chronic infusion study s uggest that uptake into tissue is not saturated, even after 28 days of infusion. Analysis of blood plasma from oligonucleotide-treated anima ls shows a possible transient elevation in levels of lactate dehydroge nase (LDH), alanine aminotransferase (ALT), and aspartate aminotransfe rase (AST), but not alkaline phosphatase (AP), gamma-glutamyltransfera se (GT), and bilirubin. The data collectively support the potential ut ility of phosphorothioate oligonucleotides as therapeutic agents in vi vo.