PHARMACOKINETIC STUDIES OF CHLOROETHYLNITROSOCARBAMOYL-AMINO ACID-DERIVATIVES INVIVO AND INVITRO

The in vitro chemosensitivity of MAC 15A ascites cells to CNC-alanylal anine and CNC-glycinemethylamide was assessed using a clonogenic assay system. In vitro stability studies and in vivo pharmacokinetics were performed using a reversed-phase HPLC technique. Initial concentration s of CNC-alanylalanine and CNC-glycinemethylamide of 5.2 mugml-1 and 3 .2 mugml-1 respectively, were required for a 70% reduction in colony f ormation of MAC 15A cells in vitro. The concentrations of active alkyl ating species generated were calculated from the drug half-lives in ti ssue culture medium. On this basis, a 70% cell kill was achieved by eq uivalent concentrations of 10.8 muM CNC-alanylalanine and 10.6 muM CNC -glycinemethylamide. Analysis of drug levels following intraperitoneal administration revealed that CNC-alanylalanine was cleared more slowl y from the peritoneal cavity producing a greater drug concentration at the site of the ascitic MAC 15A tumour. These results suggested that the superior activity of CNC-alanylalanine over CNC-glycinemethylamide against MAC 15A in vivo could be attributed mainly to differences in the pharmacokinetic behaviour of the two drugs following intraperitone al administration and that CNC-alanylalanine might have a role in the treatment of local peritoneal disease.