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OtherTOXICOLOGY

Pharmacokinetics and Distribution of a 33P-labeled Anti-Human Immunodeficiency Virus Oligonucleotide (AR177) after Single- and Multiple-Dose Intravenous Administration to Rats

Thomas L. Wallace, Scott A. Bazemore, Karsten Holm, Peter M. Markham, J. Paul Shea, Nilabh Chaudhary and Paul A. Cossum
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1480-1488;
Thomas L. Wallace
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Scott A. Bazemore
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Karsten Holm
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Peter M. Markham
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J. Paul Shea
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Nilabh Chaudhary
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Paul A. Cossum
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Abstract

AR177 is a 17-mer oligonucleotide that has anti-human immunodeficiency virus activity in vitro. The disposition of internally labeled 33P-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.

Footnotes

  • Send reprint requests to: Dr. Thomas L. Wallace, Aronex Pharmaceuticals, Inc., 3400 Research Forest Drive, The Woodlands, TX 77381.

  • ↵1 This work was supported in part by Phase I Small Business Innovation Grant 1-R43-AI38788–01 from the National Institute of Allergy and Infectious Disease (T.L.W.).

  • ↵2 These data are deposited with the American Society for Information Science (NAPS), c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10017.

  • Abbreviations:
    AUC
    area under the curve
    Cmin
    minimum plasma concentration
    HIV
    human immunodeficiency virus
    HPLC
    high-pressure liquid chromatography
    • Received July 9, 1996.
    • Accepted November 22, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherTOXICOLOGY

Pharmacokinetics and Distribution of a 33P-labeled Anti-Human Immunodeficiency Virus Oligonucleotide (AR177) after Single- and Multiple-Dose Intravenous Administration to Rats

Thomas L. Wallace, Scott A. Bazemore, Karsten Holm, Peter M. Markham, J. Paul Shea, Nilabh Chaudhary and Paul A. Cossum
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1480-1488;

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OtherTOXICOLOGY

Pharmacokinetics and Distribution of a 33P-labeled Anti-Human Immunodeficiency Virus Oligonucleotide (AR177) after Single- and Multiple-Dose Intravenous Administration to Rats

Thomas L. Wallace, Scott A. Bazemore, Karsten Holm, Peter M. Markham, J. Paul Shea, Nilabh Chaudhary and Paul A. Cossum
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1480-1488;
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