Disposition of new sulphur-containing 2-(chloroethyl)nitrosoureas in rats

Abstract

1. N'-(2-Chlorwthyl)-N-[2-(methylsulphinyl) ethyl] and N'-(2-chloroethyl)-N-[2- (methylsulphonyl) ethyl]-N and -N'-nitrosoureas (CMSOEN₁, CMSO₂EN₁, CMSOEN₂, and CMS0₂EN₂) are new nitrosoureas derived from cysteamine. Two of them (CMSOEN₂ and CMS0₂EN₂) have shown excellent efficacy against several murine tumours.

2. The inactive agents (CMSOEN₁ and CMSO₂EN₁) display low alkylating activity but high carbamoylating activity. In contrast, the active agents (CMSOEN₂ and CMSO₂EN₂) are strong alkylating agents but relatively weak carbamoylators.

3. The disposition of CMSOEN₂ and CMSO₂EN₂ was studied in rat, using two differently labelled species of each compound, administered i.v. (60 µmol/kg). Plasma disappearance, tissue distribution (with the exception of the brain) and elimination of radioactivity are similar for the two compounds similarly labelled. In contrast, these parameters are strongly influenced by the label position used.

4. Plasma disappearance of unchanged CMSOEN₂ and CMSO₂EN₂ follows a firstorder kinetic process with the same half-life for both compounds (30-31 min). More unchanged CMSO₂EN₂ is found in brain compared to its congener (55nmol/g and 37 nmol/g respectively at five minutes). This is most likely the consequence of the higher lipophilic character of the former compound.

5. The breakdown product 2-chloroethanol was identified in plasma.