Document 0401
 DOCN  M9440401
 TI    [What is known about the cellular and molecular pharmacodynamics of
       nucleosides?]
 DT    9404
 AU    Sommadossi JP; Departement de Pharmacologie, Universite d'Alabama,
       Birmingham; 35294.
 SO    Pathol Biol (Paris). 1993 Oct;41(8 Pt 2):781-7. Unique Identifier :
       AIDSLINE MED/94143073
 AB    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)
 DE    Didanosine/METABOLISM/*PHARMACOLOGY
       Dideoxyadenosine/METABOLISM/PHARMACOLOGY
       Dideoxynucleosides/METABOLISM/*PHARMACOLOGY  Drug Resistance, Microbial
       DNA Polymerases/METABOLISM  English Abstract  Hematopoietic Stem
       Cells/DRUG EFFECTS  Human  HIV-1/*DRUG EFFECTS/METABOLISM  In Vitro
       Zidovudine/*PHARMACOLOGY  JOURNAL ARTICLE  REVIEW  REVIEW, TUTORIAL

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).