Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice.
OBJECTIVE
To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts.


METHODS
Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed.


RESULTS
In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile.


CONCLUSIONS
The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs.
Morton
Christopher L
CL
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
Iacono
Lisa
L
Hyatt
Janice L
JL
Taylor
Kody R
KR
Cheshire
Pamela J
PJ
Houghton
Peter J
PJ
Danks
Mary K
MK
Stewart
Clinton F
CF
Potter
Philip M
PM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004950:Esterases / Q000172:deficiency* / Q000235:genetics; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000473:pathology; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D004950:Esterases; D002166:Camptothecin