DECAY-RATES OF ANTI-HIV DIDEOXYNUCLEOTIDES IN TISSUE-CULTURE SYSTEMS - A SIMPLE CORRECTION FOR THE EFFECT OF CELL REPLICATION

Measurement of intracellular drug levels in cell culture systems can b e of predictive value in establishing rational clinical dosage schedul es. Such in vitro measurements carried out with anti-HIV agents of the 2',3'-dideoxynucleoside (ddN) class have shown that many of the pharm acologically 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 u nperturbed rate so that a systematic dilution error occurs in the meas urement 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)-va lues for ddNTPs and for other agents with similar intracellular pharma cokinetic properties. Two factors of practical interest emerge: first, the error is greater for agents with slow intracellular clearance rat es than for agents with rapid rates; and second, for cell lines with l ong doubling times, the measured t(1/2)-values approach more closely t o the true t(1/2)values, until with the extreme case (quiescent or ''G (o)'' cells), the observed and true decay times are identical. The gre atest dilution errors are seen with adenodine-based agents such as ddA TP and 2'-F-ddATP, while the smallest errors are seen with rapidly cle ared agents of the dideoxythymidine class.