Tissue distribution and metabolism in rat of an ethynesulphonamide with filaricidal activity.

1. The tissue distribution and metabolism of a new filaricidal agent P903 (N-[(2-phenylethynyl)sulfonyl]morpholine) were studied in rat. 2.

Enhancement by O6-benzyl-N-acetylguanosine derivatives of chloroethylnitrosourea antitumor action in chloroethylnitrosourea-resistant human malignant melanocytes.

The exposure of cells to O6-methylguanine or O6-benzylguanine is known to reduce the enzymatic activity of O6-alkylguanine-DNA alkyltransferase, which leads to a sensitivity enhancement to chloroethylnitrosourea cytotoxic effects. The main disadvantage of the guanine derivatives is their low water solubility, which makes their formulation difficult for clinical use in humans. To overcome this problem, water-soluble O6-alkylguanine-DNA alkyltransferase inhibitors have been synthesized and their ability to increase the chloroethylnitrosourea potency in vitro and in vivo was evaluated.

Disposition and metabolism of O6-alkylguanine-DNA alkyltransferase inhibitor in nude mice bearing human melanoma.

Tumor resistances to chloroethylnitrosourea (CENU) are mainly due to O6-alkylguanine-DNA alkyltransferase (AGT). Our laboratory has synthesized a new water-soluble AGT inhibitor. O6-benzyl-N-acetylguanosine (BNAG).

Biodistribution and metabolism of orally administered mitozolomide in mice.

The disposition and metabolism of two 14C-labeled species of Mitozolomide (Mz) were studied in healthy and in B16 melanoma-bearing mice after po administration of a 40 mg/kg dose. Urine was the main elimination route of the radioactivity derived from [14C]chloroethyl Mz whereas a major part of the radiocarbon was recovered as 14CO2 in the expired air of mice given C]tetrazin Mz, indicating an extensive metabolism of the drug. Subsequent studies conducted only with the [14C]chloroethyl species, showed that total radioactivity and Mz were rapidly distributed to plasma and tissues but that Mz levels decreased more rapidly than those of total radioactivity, thus indicating an early metabolism of the drug.

Main urinary metabolites of two cysteamine-containing 2-(chloroethyl) nitrosoureas in rats.

Urine is the major route of excretion of N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]-N'-nitrosourea (CMSOEN2), N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (CMSO2EN2), and their metabolites in the rat. Labeling the two compounds with 14C in three different positions facilitated their metabolic study in animals. The 14C-ethyl species were chosen in order to investigate the presence of unchanged compounds and that of the denitrosated forms.