Effect of hydroxyurea and dideoxyinosine on intracellular 3'-deoxyadenosine-5'-triphosphate concentrations in HIV-infected patients.
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.
Bakshi
Rahul P
RP
Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Hamzeh
Fayez
F
Frank
Ian
I
Eron
Joseph J
JJ
Bosch
Ronald J
RJ
Rosenkranz
Susan L
SL
Cramer
Yoninah S
YS
Ussery
Michael
M
Flexner
Charles
C
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
D019380:Anti-HIV Agents; D003838:Deoxyadenine Nucleotides; C011746:3'-deoxyadenosine 5'-triphosphate; D016049:Didanosine; D006918:Hydroxyurea