Pharmacokinetics and Distribution of a 33P-labeled Anti-Human Immunodeficiency Virus Oligonucleotide (AR177) after Single- 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 33 P-AR177 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 bl...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 1997-03, Vol.280 (3), p.1480-1488
Main Authors: Wallace, T L, Bazemore, S A, Holm, K, Markham, P M, Shea, J P, Chaudhary, N, Cossum, P A
Format: Article
Language:English
Subjects:
AIDS/HIV
Animals
Anti-HIV Agents - administration & dosage
Anti-HIV Agents - blood
Anti-HIV Agents - pharmacokinetics
Anti-HIV Agents - urine
Bone Marrow - metabolism
Chromatography, High Pressure Liquid
Feces - chemistry
Injections, Intravenous
Kidney Cortex - metabolism
Liver - metabolism
Male
Oligonucleotides - administration & dosage
Oligonucleotides - blood
Oligonucleotides - pharmacokinetics
Oligonucleotides - urine
Rats
Rats, Sprague-Dawley
Tissue Distribution
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Summary:AR177 is a 17-mer oligonucleotide that has anti-human immunodeficiency virus activity in vitro . The disposition of internally labeled 33 P-AR177 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, significantly longer than values reported for other oligonucleotides. Analysis of the AR177 tissue distribution showed that the majority of the dose was distributed to the liver (40%), bone marrow (17%) and renal cortex (15%) at 8 hr after single dosing. Analysis of the AR177 concentrations in tissues showed that the highest concentrations were achieved in the renal cortex (15.0 μg-eq/g), liver (7.4 μg-eq/g), bone marrow (3.9 μg-eq/g), mesenteric lymph node (3.0 μg-eq/g) and spleen (2.4 μg-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-eight hours after the last of seven i.v. doses given every other day, the concentrations in tissues were as follows: renal cortex, 39.9 μg-eq/g; liver, 33.9 μg-eq/g; bone marrow, 12.7 μg-eq/g; spleen, 9.3 μg-eq/g; mesenteric lymph node, 5.1 μg-eq/g. Twenty-one days after administration of the last dose, tissue concentrations were still high, as follows: renal cortex, 18.6 μg-eq/g; liver, 6.2 μg-eq/g; bone marrow, 12.5 μg-eq/g; mesenteric lymph node, 3.9 μg-eq/g; spleen, 8.1 μg-eq/g. There was low urinary and fecal excretion (urinary excretion 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-performance liquid chromatography and electrophoretic analysis of the radioactivity in tissues indicated that >90% of the radioactivity represented 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 lymphoid and nonlymphoid tissues in rats.
ISSN:0022-3565
1521-0103