title: Activation of CPT-11 in mice: identification and analysis of a highly effective plasma esterase.
abstract: 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). Recently, 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 reduced 3-fold in Esl(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 vitro. In addition, pharmacokinetic studies of CPT-11 and SN-38 in these animals demonstrated approximately 5-fold less conversion to SN-38. However, extracts derived from tissues from Es1(e) animals revealed total esterase activities similar to those of control mice, and these extracts metabolized CPT-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 results suggest that the reduced levels of Es-1 esterase present in Es1(e) mice are due to down-regulation of gene transcription, and that this plasma esterase is responsible for the majority of CPT-11 metabolism in mice.
authors.affiliation: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Morton
authors.forename: M
authors.initials: M
authors.lastname: Wierdl
authors.forename: L
authors.initials: L
authors.lastname: Oliver
authors.forename: M K
authors.initials: MK
authors.lastname: Ma
authors.forename: M K
authors.initials: MK
authors.lastname: Danks
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
authors.forename: J L
authors.initials: JL
authors.lastname: Eiseman
authors.forename: P M
authors.initials: PM
authors.lastname: Potter
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D003433:Crosses, Genetic; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D004950:Esterases / Q000097:blood* / Q000235:genetics; D015870:Gene Expression; D000077146:Irinotecan; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011355:Prodrugs / Q000493:pharmacokinetics*; D014020:Tissue Extracts / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D011355:Prodrugs; D014020:Tissue Extracts; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D004950:Esterases; D002166:Camptothecin