TISSUE DISPOSITION OF ZIDOVUDINE AND ITS PHOSPHORYLATED METABOLITES IN ZIDOVUDINE-TREATED HEALTHY AND RETROVIRUS INFECTED MICE

Purpose. The purpose of this study was to examine the effect of chroni c AZT treatment on the in vivo tissue disposition of the phosphorylate d AZT metabolites in healthy and retrovirus infected mice. Methods. Fe male C57BL/6 mice at 12 weeks after inoculation with LP-BMS murine leu kemia virus as well as age-matched control animals were dosed subcutan eously 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 fi nal AZT dosing solution containing [H-3]AZT with a specific activity o f 87 mCi/mmol. The levels of AZT and its phosphorylated metabolites we re determined in tissues collected at different times after the last A ZT administration using an analytical method coupling an ion-pair HPLC separation procedure with radioactivity detection following the separ ation. Results. The tissue-to-plasma (T/P) AZT ratios in control mice could be ranked in the following order: kidneys > muscle congruent to spleen congruent to liver congruent to heart > lung congruent to thymu s > lymph nodes >> brain. The distributions of AZT into lymph nodes, l ung, and thymus tissues in infected mice increased significantly in co mparison with those of control animals. Tissue AZT 5'-monophosphate (A ZT-MP) profiles tended to parallel the AZT profiles in most tissues ex amined. 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 samp les from both control and infected animals. AZT-TP content was not det ectable in any of the brain samples analyzed. The lymph nodes of the c ontrol animals showed poor ability to phosphorylate AZT to its active triphosphate moiety. This ability was significantly enhanced in infect ed animals. Conclusions. Comparing these findings with those of our pr evious study performed following a single dose administration of AZT, the chronic AZT regimen had minimal effect on the in vivo tissue dispo sition of the phosphorylated AZT metabolites. The therapeutic implicat ions of inadequate maintenance of the level of active AZT metabolite i n the lymph nodes and the brain following chronic AZT treatment need t o be further explored.