title: Decay rates of anti-HIV dideoxynucleotides in tissue culture systems: a simple correction for the effect of cell replication.
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 "G(o)" 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.
authors.affiliation: Laboratory of Medicinal Chemistry, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Ahluwalia
authors.forename: R L
authors.initials: RL
authors.lastname: Dedrick
authors.forename: J S
authors.initials: JS
authors.lastname: Driscoll
authors.forename: P F
authors.initials: PF
authors.lastname: Morrison
authors.forename: W Y
authors.initials: WY
authors.lastname: Gao
authors.forename: D G
authors.initials: DG
authors.lastname: Johns
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D046508:Culture Techniques; D003838:Deoxyadenine Nucleotides / Q000493:pharmacokinetics*; D054306:Dideoxynucleotides; D006207:Half-Life; D006801:Humans
chemical_list: D019380:Anti-HIV Agents; D003838:Deoxyadenine Nucleotides; D054306:Dideoxynucleotides; C108017:2',3'-dideoxy-2'-fluoroadenosine triphosphate; C037773:2',3'-dideoxyadenosine triphosphate; D000255:Adenosine Triphosphate