In vivo tissue disposition of 3'-azido-3'-deoxythymidine and its anabolites in control and retrovirus-infected mice.
At present, 3'-azido-3'-deoxythymidine (AZT; zidovudine) remains the drug of choice for initiating AIDS therapy. This drug in itself is inactive; it needs to be converted intracellularly by a series of cellular kinases to AZT 5'-triphosphate (AZT-TP) to exert antiviral activity. The purpose of this study was to examine the in vivo disposition of the phosphorylated AZT anabolites in different target tissues and to investigate the effects of chronic retrovirus infection on the tissue disposition of AZT anabolites. Female C57BL/6 mice at 20 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. The dosing solution contained [3H]AZT with a specific activity of 87 mCi/mmol. The levels of AZT and its phosphorylated anabolites were determined in tissues collected at different times after AZT administration using an analytical method coupling an ion-pair HPLC separation procedure with radioactivity detection after the separation. The tissue-to-plasma 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 approximately equal to lung > thymus > lymph nodes > brain. Similar rank order was observed in infected animals, with the exception that significantly higher AZT levels were found in the lymph nodes, where the tissue-to-plasma AZT ratios in lymph nodes were higher than those in thymus tissues. Tissue AZT 5'-monophosphate profiles tended to parallel the AZT profiles in most tissues examined. Delays in the appearance of AZT 5'-diphosphate and AZT-TP were observed in all tissues tested. AZT-TP content was not detectable in any of the brain samples analyzed. The conversion of AZT to AZT anabolites was found to be highest in the spleen and bone marrow samples from both control and infected animals. 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. We concluded that the in vivo disposition of AZT anabolites after a single dose administration of AZT is tissue-specific in mice and that experimentally induced chronic retrovirus infection resulted in the most significant changes in the distribution of AZT into the lymph nodes and in the phosphorylation of AZT in this important target tissue. Further studies are needed to relate the tissue-specific disposition of AZT anabolites to the therapeutic problems encountered with AZT treatment.
Chow
H H
HH
Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson 85721, USA.
Li
P
P
Brookshier
G
G
Tang
Y
Y
D000818:Animals; D005260:Female; D009052:Leukemia Virus, Murine / Q000302:isolation & purification; D051379:Mice; D008810:Mice, Inbred C57BL; D012192:Retroviridae Infections / Q000378:metabolism*; D014018:Tissue Distribution; D015215:Zidovudine / Q000097:blood / Q000493:pharmacokinetics*
D015215:Zidovudine