MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wadkins, R. M.
Right arrow Articles by Potter, P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wadkins, R. M.
Right arrow Articles by Potter, P. M.

Vol. 60, Issue 2, 355-362, August 2001

Structural Constraints Affect the Metabolism of 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) by Carboxylesterases

Randy M. Wadkins, Christopher L. Morton, James K. Weeks, LaGora Oliver, Monika Wierdl, Mary K. Danks, and Philip M. Potter

Johns Hopkins University School of Medicine, Baltimore, Maryland (R.M.W.); and Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.L.M., J.K.L., L.O., M.W., M.K.D., P.L.P.)

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin [CPT-11 (irinotecan)] is a water-soluble camptothecin-derived prodrug that is activated by esterases to yield the potent topoisomerase I poison SN-38. We identified a rabbit liver carboxylesterase (CE) that was very efficient at CPT-11 metabolism; however, a human homolog that was more than 81% identical to this protein activated the drug poorly. Recently, two other human CEs have been isolated that are efficient in the conversion of CPT-11 to SN-38, yet both demonstrate little homology to the rabbit protein. To understand this phenomenon, we have characterized a series of esterases from human and rabbit, including several chimeric proteins, for their ability to metabolize CPT-11. Computer predictive modeling indicated that the ability of each enzyme to activate CPT-11 was dependent on the size of the entrance to the active site. Kinetic studies with a series of nitrophenyl and naphthyl esters confirmed these predictions, indicating that activation of CPT-11 by a CE is constrained by size-limited access of the drug to the active site catalytic amino acid residues.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
S. Takahashi, M. Katoh, T. Saitoh, M. Nakajima, and T. Yokoi
Different Inhibitory Effects in Rat and Human Carboxylesterases
Drug Metab. Dispos., May 1, 2009; 37(5): 956 - 961.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
E. T. Williams, K. O. Jones, G. D. Ponsler, S. M. Lowery, E. J. Perkins, S. A. Wrighton, K. J. Ruterbories, M. Kazui, and N. A. Farid
The Biotransformation of Prasugrel, a New Thienopyridine Prodrug, by the Human Carboxylesterases 1 and 2
Drug Metab. Dispos., July 1, 2008; 36(7): 1227 - 1232.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
K. Masaki, M. Taketani, and T. Imai
FIRST-PASS HYDROLYSIS OF A PROPRANOLOL ESTER DERIVATIVE IN RAT SMALL INTESTINE
Drug Metab. Dispos., March 1, 2006; 34(3): 398 - 404.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
K. J. P. Yoon, J. L. Hyatt, C. L. Morton, R. E. Lee, P. M. Potter, and M. K. Danks
Characterization of inhibitors of specific carboxylesterases: Development of carboxylesterase inhibitors for translational application
Mol. Cancer Ther., August 1, 2004; 3(8): 903 - 909.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
R. M. Wadkins, J. L Hyatt, K. J. P. Yoon, C. L. Morton, R. E. Lee, K. Damodaran, P. Beroza, M. K. Danks, and P. M. Potter
Discovery of Novel Selective Inhibitors of Human Intestinal Carboxylesterase for the Amelioration of Irinotecan-Induced Diarrhea: Synthesis, Quantitative Structure-Activity Relationship Analysis, and Biological Activity
Mol. Pharmacol., June 1, 2004; 65(6): 1336 - 1343.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
M. Rooseboom, J. N. M. Commandeur, and N. P. E. Vermeulen
Enzyme-Catalyzed Activation of Anticancer Prodrugs
Pharmacol. Rev., March 1, 2004; 56(1): 53 - 102.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
K. J. P. Yoon, E. J. Krull, C. L. Morton, W. G. Bornmann, R. E. Lee, P. M. Potter, and M. K. Danks
Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies
Mol. Cancer Ther., November 1, 2003; 2(11): 1171 - 1181.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
I. Kim, X.-y. Chu, S. Kim, C. J. Provoda, K.-D. Lee, and G. L. Amidon
Identification of a Human Valacyclovirase: BIPHENYL HYDROLASE-LIKE PROTEIN AS VALACYCLOVIR HYDROLASE
J. Biol. Chem., July 3, 2003; 278(28): 25348 - 25356.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
M. Xie, D. Yang, M. Wu, B. Xue, and B. Yan
Mouse Liver and Kidney Carboxylesterase (M-LK) Rapidly Hydrolyzes Antitumor Prodrug Irinotecan and the N-Terminal Three Quarter Sequence Determines Substrate Selectivity
Drug Metab. Dispos., January 1, 2003; 31(1): 21 - 27.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics