Tissue disposition of zidovudine and its phosphorylated metabolites in zidovudine-treated healthy and retrovirus infected mice.

Abstract

The purpose of this study was to examine the effect of chronic AZT treatment on the in vivo tissue disposition of the phosphorylated AZT metabolites in healthy and retrovirus infected mice. Female C57BL/6 mice at 12 weeks after inoculation with LP-BM5 murine leukemia virus as well as age-matched control animals were dosed subcutaneously with 25 mg/kg of AZT twice a day for 8 weeks. At the end of the 8-wk treatment (20 weeks post inoculation), each animal received a final AZT dosing solution containing [3H]-AZT with a specific activity of 87 mCi/mmol. The levels of AZT and its phosphorylated metabolites were determined in tissues collected at different times after the last AZT administration using an analytical method coupling an ion-pair HPLC separation procedure with radioactivity detection following the separation. The tissue-to-plasma (T/P) AZT ratios in control mice could be ranked in the following order: kidneys > muscle approximately equal to spleen approximately equal to liver approximately equal to heart > lung approximately equal to thymus > lymph nodes >> brain. The distributions of AZT into lymph nodes, lung, and thymus tissues in infected mice increased significantly in comparison with those of control animals. Tissue AZT 5'-monophosphate (AZT-MP) profiles tended to parallel the AZT profiles in most tissues examined. Delays in the appearance of AZT 5'-diphosphate (AZT-DP) and AZT-TP were observed in all tissues tested. The conversion of AZT to AZT metabolites was found to be highest in the spleen and bone marrow samples from both control and infected animals. AZT-TP content was not detectable in any of the brain samples analyzed. The lymph nodes of the control animals showed poor ability to phosphorylate AZT to its active triphosphate moiety. This ability was significantly enhanced in infected animals. Comparing these findings with those of our previous study performed following a single dose administration of AZT, the chronic AZT regimen had minimal effect on the in vivo tissue disposition of the phosphorylated AZT metabolites. The therapeutic implications of inadequate maintenance of the level of active AZT metabolite in the lymph nodes and the brain following chronic AZT treatment need to be further explored.