Activation of CPT-11 in mice: Identification and analysis of a highly effective plasma esterase

The camptothecin prodrug CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1 -piperidino]carbonyloxycamptothecin) is converted by esterases to yield the potent topoisomerase I poison SN-38 (7-ethyl-10-hydroxycamptothecin), Rece ntly, a mouse strain (Es1(e)) has been identified that demonstrates reduced plasma esterase activity, and we have monitored the ability of plasma from these mice to metabolize CPT-11, Total plasma esterase activity was reduce d 3-fold in Es1(e) mice in comparison to control mice, and this resulted in a 200-fold reduction in SN-38 production after incubation with CPT-11 in v itro. In addition, pharmacokinetic studies of CPT-11 and SN-38 in these ani mals demonstrated approximately 5-fold less conversion to SN-38, However, e xtracts derived from tissues from Es1(e) animals revealed total esterase ac tivities similar to those of control mice, and these extracts metabolized C PT-11 with equal efficiency. Northern analysis of RNA isolated from organs indicated that the liver was the primary source of Es-1 gene expression and that very low levels of Es-1 RNA were present in Es1(e) mice. These result s suggest that the reduced levels of Es-1 esterase present in Es1(e) mice a re due to down-regulation of gene transcription, and that this plasma ester ase is responsible for the majority of CPT-11 metabolism in mice.