Intracellular phosphorylation of zidovudine in an in vitro hollow fiber model.
Combination antiretroviral therapy that includes zidovudine has proved much better in treating human immunodeficiency virus infection than monotherapy Diminished responses to zidovudine, especially when it was given alone, was likely due to factors including interpatient variability in pharmacokinetics, nonadherence, emergence of resistant mutants, and reduced cellular enzymatic processes to phosphorylate the drug. This study evaluated the intracellular metabolism of zidovudine up to 6 weeks using a hollow fiber cellular model system that simulated exposure of cells to steady-state concentrations achieved in humans. The CEM-T4 lymphocytes were exposed to simulated 200-, 600-, and 1200-mg daily doses of zidovudine. Samples were analyzed for monophosphate, diphosphate, and triphosphate metabolites of zidovudine by high-performance liquid chromatography separation and radiochemical detection. The monophosphate metabolite increased as simulated doses increased, but no corresponding increases in the active triphosphate metabolite occurred. In addition, intracellular metabolism of zidovudine did not change after exposure for 6 weeks. These results suggest that the active triphosphate metabolite of zidovudine does not change much when doses are increased or when exposed for at least 6 weeks. Hollow fiber models may be used effectively to investigate intracellular metabolism of antiviral agents and for some duration of time.
Rana
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KZ
Antiinfective Pharmacology Research Unit, University of Rhode Island College of Pharmacy, Roger Williams Medical Center, Providence 02908, USA.
Dudley
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MN
D019380:Anti-HIV Agents / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D010710:Phosphates / Q000032:analysis; D010766:Phosphorylation; D011854:Radiochemistry; D013997:Time Factors; D015215:Zidovudine / Q000378:metabolism*
D019380:Anti-HIV Agents; D010710:Phosphates; D015215:Zidovudine