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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


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