THE ROLE OF CARBOXYLESTERASES IN THE BIOTRANSFORMATION OF A RADIONUCLIDE DECORPORATION AGENT DTPA PENTA-ETHYL ESTER PRODRUG

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  • March 19, 2019
Creator
  • Fu, Jing
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • A penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (C2E5) was developed for radionuclide decorporation. Previous studies of C2E5 delivered by oral and transdermal routes in rats suggested that the prodrug is metabolized to C2E2, and not the active drug DTPA. Although it was later determined that C2E2 is an active drug, it is unknown if C2E5 is converted into C2E2 and/or DTPA in humans, and whether C2E5 metabolic mechanisms affect its delivery. Therefore, the objectives of this study were to investigate the hepatic, intestinal and plasma hydrolysis of C2E5 hydrolysis in preclinical species and humans, identify the human CESs (CESs) isoforms that hydrolyze C2E5, evaluate the biotransformation of C2E5 by CESs in human skin, and determine the effect of excipients on transdermal C2E5 hydrolysis. Hydrolysis of C2E5 was assessed using S9 fractions from human, dog and rat tissues, and human recombinant CESs in the absence or presence of an esterase inhibitor. The data revealed interspecies differences in C2E5 metabolism caused by differences in CES expression profiles, and demonstrated that C2E5 metabolism in dog and rat is not representative of its metabolism in humans. Therefore, further studies were conducted using S9 fractions from human keratinocyte cell lines and CES-specific inhibitor to determine the contributions of individual CESs to C2E5 metabolism in human skin. Data analysis by LC/MS/MS revealed that C2E5 is hydrolyzed by CESs in human keratinocytes, with a primary metabolic role for CES1. Since cutaneous metabolism contributes to C2E5 transdermal delivery, 12 common excipients used in transdermal formulations were analyzed for their potential to alter C2E5 hydrolysis by human skin. Significant inhibition of C2E5 metabolism was observed with Miglyol 840, Eudragit RLPO, Crodamol EO-LQ-(MH), Brij 72, sodium lauryl sulfate and Tween 20, at concentrations of 100 µg/ml, whereas Eudragit RSPO enhanced C2E5 hydrolysis. Overall, this research project provides important insights into C2E5 metabolism through oral and transdermal delivery routes in humans that could impact multiester-based prodrug development.
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  • In Copyright
Advisor
  • Liu, Zhi
  • Thakker, Dhiren
  • Jay, Michael
  • Hingtgen, Shawn
  • Xiao, Xiao
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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