Short-term (13-week) toxicity study of 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), a novel anti-HIV and contraceptive agent, in B6C3F1 mice

The zidovudine derivative, WHI-07 (5-bromo-6-methoxy-5,6-dihydro3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate), is a dual-function spermicidal agent with potent anti-HIV activity. In this study, groups of 20 female B6C3F1 mice were exposed intravaginally to a gel microemulsion containing 0, 0.5, 1.0, or 2.0% WHI-07, 5 days per week for 13 consecutive weeks. On a molar basis, these concentrations of WHI-07 are 1400- to 5700-times higher than its spermicidal ECS, and 1.4 x 10(6) to 5.7 x 106 times higher than its in vitro anti-HIV IC50. After 13 weeks of intravaginal treatment, mice were evaluated for toxicity. The endpoints that were used for evaluation included survival, body weight, hematologic and clinical chemistry profiles, absolute and relative organ weights, and histopathology. No effects related to WHI-07 treatments were observed on survival, mean body weight, and mean body-weight gain. Repeated intravaginal exposure of mice to WKI-07 for 13 weeks had no toxicologically significant effect on organ weights, and did not cause any adverse changes in hematology parameters or blood chemistry profiles. Extensive histopathologic examination of tissues showed no lesions of pathologic significance. Thus, intravaginal application of WHI-07, for up to 13 weeks, does not cause systemic toxicity.