0090-9556/97/2507-0893-0000$0/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 7

SHORT 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

Laboratory of Medicinal Chemistry (G.S.A., J.S.D., D.G.J.), Division of Basic Sciences, Experimental Retrovirology Branch (W.-Y.G.), Division of Clinical Sciences, National Cancer Institute; and Biomedical Engineering and Instrumentation Program (R.L.D., P.F.M.), National Center for Research Resources, National Institutes of Health

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 t_1/2-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 t_1/2-values approach more closely to the true t_1/2-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.