Disposition in mice of 7-hydroxystaurosporine, a protein kinase inhibitor with antitumor activity.

UCN-01, a hydroxylated derivative of staurosporine, was selected for study because of its promising antitumor activity. For mice dosed intravenously, subcutaneously, or by oral gavage with this compound, the maximum tolerated doses (MTD) were 20, 10, and > 100 mg/kg, respectively. UCN-01 was stable in mouse and dog plasma, but in human plasma it was converted to a metabolite in a process not inhibited by standard protease and esterase inhibitors. Following an intravenous dose of 10 mg/kg UCN-01, the half-lives for the initial (t1/2 alpha) and terminal (t1/2 beta) exponential phases of elimination were 10 and 85 min, respectively; the area under the plasma concentration-time curve (AUC value) was 117 micrograms min ml-1. In mice dosed by oral gavage with 10 mg/kg, the calculated value for the half-life of the elimination phase was 150 min. The AUC value was 15 micrograms min ml-1, giving a value for bioavailability of 13%. After subcutaneous dosing with 10 mg/kg, the calculated values for half-lives for the distribution and elimination phases were 23 and 130 min, respectively; the AUC value was 113 micrograms min ml-1. Since this value is equivalent to that obtained for intravenous dosing, administration of UCN-01 by the subcutaneous route may be an alternative to intravenous dosing in preclinical and clinical trials.

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.