Anomalous accumulation and decay of 2',3'-dideoxyadenosine-5'-triphosphate in human T-cell cultures exposed to the anti-HIV drug 2',3'-dideoxyinosine.
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).
Ahluwalia
G
G
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Cooney
D A
DA
Hartman
N R
NR
Mitsuya
H
H
Yarchoan
R
R
Fridland
A
A
Broder
S
S
Johns
D G
DG
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003838:Deoxyadenine Nucleotides / Q000493:pharmacokinetics*; D016049:Didanosine / Q000494:pharmacology*; D016048:Dideoxyadenosine / Q000494:pharmacology; D054306:Dideoxynucleotides; D006678:HIV / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism; D012254:Ribavirin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
D000998:Antiviral Agents; D003838:Deoxyadenine Nucleotides; D054306:Dideoxynucleotides; C037773:2',3'-dideoxyadenosine triphosphate; D012254:Ribavirin; D016048:Dideoxyadenosine; D007168:IMP Dehydrogenase; D016049:Didanosine