PHARMACOKINETICS AND DISTRIBUTION OF A P-33 LABELED ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS OLIGONUCLEOTIDE (AR177) AFTER SINGLE-DOSE AND MULTIPLE-DOSE INTRAVENOUS ADMINISTRATION TO RATS

AR177 is a 17-mer oligonucleotide that has anti-human immunodeficiency virus activity in vitro. The disposition of internally labeled P-33-A R177 was studied after the tail vein injection of single and multiple doses (0.7 mg/kg) to rats. After a single dose, the terminal half-life of AR177 in the blood and plasma was 367 and 271 hr, respectively, si gnificantly longer than values reported for other oligonucleotides. An alysis of the AR177 tissue distribution showed that the majority of th e dose was distributed to the liver (40%), bone marrow (17%) and renal cortex (15%) at 8 hr after single dosing. Analysis of the AR177 conce ntrations in tissues showed that the highest concentrations were achie ved in the renal cortex (15.0 mu g-eq/g), liver (7.4 mu g-eq/g), bone marrow (3.9 mu g-eq/g), mesenteric lymph node (3.0 mu g-eq/g) and sple en (2.4 mu g-eq/g) at 8 hr after single dosing. The half-life in these tissues was 9.6, 7.7, 36.8, 10.0 and 30.8 days, respectively. Forty-e ight hours after the last of seven i.v. doses given every other day, t he concentrations in tissues were as follows: renal cortex, 39.9 mu g- eq/g; liver, 33.9 mu g-eq/g; bone marrow, 12.7 mu g-eq/g; spleen, 9.3 mu g-eq/g; mesenteric lymph node, 5.1 mu g-eq/g, Twenty-one days after administration of the last dose, tissue concentrations were still hig h, as follows: renal cortex, 18.6 mu g-eq/g; liver, 6.2 mu g-eq/g; bon e marrow, 12.5 mu g-eq/g; mesenteric lymph node, 3.9 mu g-eq/g; spleen , 8.1 mu g-eq/g. There was low urinary and fecal excretion (urinary ex cretion of 12.8% and fecal excretion of 6.0% of the total dose over 21 days) after a single dose. Gel filtration and anion-exchange high-per formance liquid chromatography and electrophoretic analysis of the rad ioactivity in tissues indicated that >90% of the radioactivity represe nted intact AR177 for at least 7 days after drug dosing. These results demonstrate that AR177 has an extended plasma, blood and tissue half- life, is widely distributed and achieves high concentrations in lympho id and nonlymphoid tissues in rats.