TY - JOUR T1 - Decay Rates of Anti-HIV Dideoxynucleotides in Tissue Culture Systems: A Simple Correction for the Effect of Cell Replication JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 893 LP - 000 VL - 25 IS - 7 AU - Gurpreet S. Ahluwalia AU - Robert L. Dedrick AU - John S. Driscoll AU - Paul F. Morrison AU - Wen-Yi Gao AU - David G. Johns Y1 - 1997/07/01 UR - http://dmd.aspetjournals.org/content/25/7/893.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -