title: Effect of hydroxyurea and dideoxyinosine on intracellular 3'-deoxyadenosine-5'-triphosphate concentrations in HIV-infected patients.
abstract: Hydroxyurea (HU) significantly enhances the antiretroviral effects of the adenosine analog reverse transcriptase inhibitor dideoxyinosine (ddI). This is believed to be due to a reduction in intracellular de-oxyadenosine triphosphate (dATP) concentrations resulting from HU-mediated inhibition of ribonucleotide reductase (RnR). The effect of combined HU-ddI treatment on intracellular dATP pools in vivo has not been examined. We measured intracellular dATP concentrations in peripheral blood mononuclear cells (PBMCs) from 69 HIV-infected patients receiving 1000 or 1500 mg HU daily for 14 days, 200 mg ddI twice daily for 14 days, or a combination of the two drugs. Median intracellular dATP concentrations decreased from base-line to day 14 by 46% in the ddI + 1000 mg HU arm and by 62% in the ddI + 1500 mg HU arm. When compared to the HU monotherapy arms, these changes proved statistically significant (p = 0.018; stratified Wilcoxon rank-sum test). These findings support reduced intracellular dATP as the mechanism of ddI-HU synergistic activity, and indicate that changes in intracellular nucleotides contribute to HU activity and toxicity in patients. Since a significant reduction in dATP was measurable only when ddI was combined with HU, the antiretroviral activity of ddI may be more complex than previously assumed.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA.
authors.forename: Rahul P
authors.initials: RP
authors.lastname: Bakshi
authors.forename: Fayez
authors.initials: F
authors.lastname: Hamzeh
authors.forename: Ian
authors.initials: I
authors.lastname: Frank
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Bosch
authors.forename: Susan L
authors.initials: SL
authors.lastname: Rosenkranz
authors.forename: Yoninah S
authors.initials: YS
authors.lastname: Cramer
authors.forename: Michael
authors.initials: M
authors.lastname: Ussery
authors.forename: Charles
authors.initials: C
authors.lastname: Flexner
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003600:Cytosol / Q000737:chemistry*; D003838:Deoxyadenine Nucleotides / Q000032:analysis*; D016049:Didanosine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D006918:Hydroxyurea / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D003838:Deoxyadenine Nucleotides; C011746:3'-deoxyadenosine 5'-triphosphate; D016049:Didanosine; D006918:Hydroxyurea