Metabolism and disposition of a thiazolobenzimidazole active against human immunodeficiency virus-1

This study was undertaken to evaluate the disposition of the thiazolobenzimidazole, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TZB), which has promising antiviral activity. For mice, the maximum tolerated intravenous dose of TZB was 50 mg/kg. An HPLC procedure developed for TZB was used to determine the distribution of the drug. TZB showed no measurable binding to plasma proteins. With intravenous dosing, the kinetic values for TZB in plasma and in each of five tissues were similar in that there was an initial, short alpha-phase (1.8-7.2 min) and a longer beta phase (38-68 min). The concentrations in liver were higher than those in plasma and other tissues. For mice dosed subcutaneously with TZB, the AUC value for plasma was considerably lower than that for mice dosed intravenously; mice dosed intraperitoneally had higher plasma levels of the drug than after oral or subcutaneous dosing. No intact drug could be detected in the plasma of mice dosed topically. After intravenous, oral, or subcutaneous dosing, urinary excretion of intact TZB was < 2% of the dose. Of several vehicles tested in an attempt to increase the plasma levels of unchanged TZB in mice dosed orally, 40% hydroxypropyl beta-cyclodextrin was most effective. Two metabolites present in plasma and urine of mice were tentatively identified as the axial and equatorial sulfoxide isomers of TZB; a third, minor metabolite, was tentatively designated as the sulfone. Although the compound has activity against HIV-1, its low solubility and extensive metabolism reduce its potential for clinical use.