Hoggard P, Gibbons S, Wilkins E, Veal G, Barry M, Khoo S, Back D; International Conference on AIDS.

Int Conf AIDS. 1996 Jul 7-12; 11: 286 (abstract no. Tu.B.2125).

University of Liverpool, Liverpool, UK.

Background. Zidovudine (ZDV) requires intracellular phosphorylation to ZDV-triphosphate prior to the inhibition of HIV replication. The effect of ZDV dose on the formation of intracellular phosphorylated metabolites may help define the optimum daily dose of ZDV, which is still unknown. Methods. The plasma and intracellular phosphorylated metabolite concentrations of ZDV were determined over a 12 h period following oral administration of ZDV 100 mg and ZDV 300 mg to 10 HIV seropositive patients at steady state during two dosing regimens i.e. 100 mg t.d.s. (300 mg/day) and 300 mg b.d. (600 mg/day). The intracellular ZDV phosphates, ZDV-monophosphate (ZDV-MP), ZDV-diphosphate (ZDV-DP) and ZDV-triphosphate (ZDV-TP) were measured in peripheral blood mononuclear cells using a combination of high performance liquid chromatography (HPLC) and radioimmunoassay. Results. There was a greater than three fold increase in maximum plasma concentration (Cmax) following ZDV 300 mg when compared with ZDV 100 mg (2.69 plus or minus 0.51 versus 0.77 plus or minus 0.14 micromolars; mean plus or minus s.d.). The area under the concentration time curve (AUC0-12h) was also significantly increased (5.68 plus or minus 0.95 versus 2.14 plus or minus 0.57 micromolarsol.L-1.h) following ZDV 300 mg dose. For total intracellular ZDV phosphate metabolites the AUC0-12h was doubled (7.64 plus or minus 3.67 versus 3.71 plus or minus 1.83 pmoles. 106cells-1.h) in patients taking 300 mg compared with 100 mg. The AUC0-12h for ZDV-MP was significantly increased at the higher dose (6.47 plus or minus 3.14 versus 2.77 plus or minus 1.70 pmoles. 106cells-1.h) whereas the active moiety ZDV-TP was not significantly different (0.42 plus or minus 0.42 versus 0.61 plus or minus 0.81 pmoles. 106cells-1.h) following ZDV 100 mg and 300 mg. Conclusions. Administration of ZDV 100 mg orally produces similar concentrations of the active metabolite, ZDV-TP, and significantly less of the potentially toxic metabolite, ZDV-MP, when compared with ZDV 300 mg orally. This finding supports clinical data indicating the efficacy of low dose (300 mg/day) ZDV. The measurement of ZDV intracellular phosphorylated metabolites represents a significant advance in our understanding of the clinical pharmacology of the drug.

Publication Types:

• Meeting Abstracts

Keywords:

• 3'-azido-3'-deoxythymidine 5'-triphosphate
• Acquired Immunodeficiency Syndrome
• Chromatography, High Pressure Liquid
• Cytoplasm
• HIV Infections
• HIV Seropositivity
• Humans
• Leukocytes
• Radioimmunoassay
• Thymine Nucleotides
• Zidovudine

Other ID:

• 96922332

UI: 102218231

From Meeting Abstracts