[What is known about the cellular and molecular pharmacodynamics of nucleosides?].
3'-azido-3'-deoxythymidine (zidovudine-AZT) was the first clinically approved reverse transcriptase inhibitor for the treatment of acquired immunodeficiency syndrome (AIDS) and recently, 2',3'-dideoxyinosine (didanosine-ddI) has also been approved in France. These nucleoside analogs have no intrinsic anti-HIV activity and must be metabolized to their respective 5'-triphosphates by means of kinases, nucleotidases, or other activating enzymes present naturally in cells. The presence and activity of the necessary intracellular enzymes for activation of nucleoside analogs is highly dependent on species, cell type, and cell cycle stage, illustrating the importance of cellular functions in the mechanism(s) of action or toxicity of nucleoside analogs. Although the apparent plasma elimination half-life of the parent drug varies between 1 and 2 hours, the active triphosphate derivatives have intracellular half-lives between 4 and 12 h with 2',3'-dideoxyadenosine-5'-triphosphate (ddATP), the active component of ddl being one of the most stable with an intracellular half-life of 8 to 12 hours which result in relatively infrequent dosing as compared to other classes of potential anti-HIV drugs under development. The multifactorial mechanism(s) of toxicity of this class of drugs likely explains the different spectrums of toxicity observed with the various nucleoside analogs, and demonstrates the uniqueness of each compound. Recently, AZT-resistant strains have been isolated from AZT-treated patients, probably reflecting a sequential acquisition of amino-acid mutations in the HIV-RT. Of importance, cross-resistance was demonstrated with other compounds with an 3'-azido group, but no cross-resistance was detected with either ddl of 2',3'-dideoxycytidine.(ABSTRACT TRUNCATED AT 250 WORDS)
Sommadossi
J P
JP
Département de Pharmacologie, Université d'Alabama, Birmingham 35294.
D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D016049:Didanosine / Q000378:metabolism / Q000494:pharmacology*; D016048:Dideoxyadenosine / Q000378:metabolism / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000378:metabolism / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015215:Zidovudine / Q000494:pharmacology*
D015224:Dideoxynucleosides; D015215:Zidovudine; D016048:Dideoxyadenosine; D004259:DNA-Directed DNA Polymerase; D016049:Didanosine
Que sait-on sur la pharmacodynamie cellulaire et moléculaire des nucléosides?