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Research ArticleArticle

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
Molecular Pharmacology August 2001, 60 (2) 355-362; DOI: https://doi.org/10.1124/mol.60.2.355
Randy M. Wadkins
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Christopher L. Morton
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James K. Weeks
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LaGora Oliver
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Monika Wierdl
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Mary K. Danks
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Philip M. Potter
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Abstract

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.

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Molecular Pharmacology: 60 (2)
Molecular Pharmacology
Vol. 60, Issue 2
1 Aug 2001
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Research ArticleArticle

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
Molecular Pharmacology August 1, 2001, 60 (2) 355-362; DOI: https://doi.org/10.1124/mol.60.2.355

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Research ArticleArticle

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
Molecular Pharmacology August 1, 2001, 60 (2) 355-362; DOI: https://doi.org/10.1124/mol.60.2.355
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