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Rapid CommunicationShort Communication

Decay Rates of Anti-HIV Dideoxynucleotides in Tissue Culture Systems: A Simple Correction for the Effect of Cell Replication

Gurpreet S. Ahluwalia, Robert L. Dedrick, John S. Driscoll, Paul F. Morrison, Wen-Yi Gao and David G. Johns
Drug Metabolism and Disposition July 1997, 25 (7) 893-000;
Gurpreet S. Ahluwalia
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Robert L. Dedrick
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John S. Driscoll
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Paul F. Morrison
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Wen-Yi Gao
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David G. Johns
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Abstract

Measurement of intracellular drug levels in cell culture systems can be of predictive value in establishing rational clinical dosage schedules. Such in vitro measurements carried out with anti-HIV agents of the 2′,3′-dideoxynucleoside (ddN) class have shown that many of the pharmacologically active ddNTP metabolites of these agents have relatively long intracellular half-lives and little or no host-cell cytotoxicity. As a consequence, replication of drug-exposed cells continues at an unperturbed rate so that a systematic dilution error occurs in the measurement of ddNTP decay half-times. The aim of this study is to present a simple general formulation for the correction of measured t1/2-values for ddNTPs and for other agents with similar intracellular pharmacokinetic properties. Two factors of practical interest emerge: first, the error is greater for agents with slow intracellular clearance rates than for agents with rapid rates; and second, for cell lines with long doubling times, the measured t1/2-values approach more closely to the true t1/2-values, until with the extreme case (quiescent or "G0" cells), the observed and true decay times are identical. The greatest dilution errors are seen with adenodine-based agents such as ddATP and 2′-F-ddATP, while the smallest errors are seen with rapidly cleared agents of the dideoxythymidine class.

Footnotes

  • Send reprint requests to: Dr. David G. Johns, Building 37, Room 5B22, Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute/National Institutes of Health, Bethesda, MD 20892-4255.

  • Received September 11, 1996; accepted March 25, 1997.

  • Abbreviations used are::
    ddN
    2′,3′-dideoxynucleoside
    HIV
    human immunodeficiency virus
    ddNTP
    ddN-5′-triphosphate
    ddATP
    2′,3′-dideoxyadenosine-5′-triphosphate
    F-ddATP
    2′-β-fluoro-ddATP
    ddI
    2′,3′-dideoxyinosine
    F-ddA
    2′-β-fluoro-2′,3′-dideoxyadenosine
    ddGTP
    2′,3′-dideoxyguanosine-5′-triphosphate
    PBM cells
    peripheral blood mononuclear cells
    D4T
    2′,3′-didehydro-3′-deoxythymidine
    PHA
    phytohemagglutinin
    tm
    measured (uncorrected)t1/2
    tD
    cell doubling time
    3TC-TP
    2′-deoxy-3′-thiacytidine-5′-triphosphate
    AZT
    3′-azido-3′-deoxythymidine
    ddC
    2′,3′-dideoxycytidine
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 7
1 Jul 1997
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Rapid CommunicationShort Communication

Decay Rates of Anti-HIV Dideoxynucleotides in Tissue Culture Systems: A Simple Correction for the Effect of Cell Replication

Gurpreet S. Ahluwalia, Robert L. Dedrick, John S. Driscoll, Paul F. Morrison, Wen-Yi Gao and David G. Johns
Drug Metabolism and Disposition July 1, 1997, 25 (7) 893-000;

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Rapid CommunicationShort Communication

Decay Rates of Anti-HIV Dideoxynucleotides in Tissue Culture Systems: A Simple Correction for the Effect of Cell Replication

Gurpreet S. Ahluwalia, Robert L. Dedrick, John S. Driscoll, Paul F. Morrison, Wen-Yi Gao and David G. Johns
Drug Metabolism and Disposition July 1, 1997, 25 (7) 893-000;
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