PT  - JOURNAL ARTICLE
AU  - G Ahluwalia
AU  - D A Cooney
AU  - N R Hartman
AU  - H Mitsuya
AU  - R Yarchoan
AU  - A Fridland
AU  - S Broder
AU  - D G Johns
TI  - Anomalous accumulation and decay of 2',3'-dideoxyadenosine-5'-triphosphate in human T-cell cultures exposed to the anti-HIV drug 2',3'-dideoxyinosine.
DP  - 1993 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 369--376
VI  - 21
IP  - 2
4099  - http://dmd.aspetjournals.org/content/21/2/369.short
4100  - http://dmd.aspetjournals.org/content/21/2/369.full
SO  - Drug Metab Dispos1993 Mar 01; 21
AB  - The rates of accumulation and decay of 2',3'-dideoxyadenosine-5'-triphosphate (ddATP) have been examined after incubation with the anti-human immunodeficiency virus (HIV) agents 2',3'-dideoxyinosine (ddIno) and 2',3'-dideoxyadenosine (ddAdo) in human T-cell systems frequently used for assay of anti-HIV agents (MOLT-4 and CEM). Formation of ddATP from ddIno or ddAdo was rapid and concentration-dependent, with no saturation of phosphorylation being observed up to extremely high levels (1 mM) of drug. Rates of removal of ddATP from MOLT-4 cells were slow (t1/2 = 25-40 hr) and appeared to be monophasic. These unusually long half-times for ddATP utilization are not a general property of purine dideoxypurine nucleosides: when the corresponding guanine analog (2',3'-dideoxyguanosine) was examined under the same conditions, the t1/2 of ddGTP removal was only 3-5 hr. Similar results were observed with the human T-cell line CCRF-CEM. Coadministration with ddIno of inosine monophosphate dehydrogenase inhibitors, such as ribavirin and tiazofurin, yielded higher levels of ddATP in MOLT-4 and CEM cells, but did not influence the slow removal of ddATP from T-cells. The long half-time for disappearance of ddATP from cells may permit the maintenance of pharmacologically effective levels of ddATP within cells with relatively infrequent administration of the parent drug (ddIno or ddAdo).