The stability of methyl-, ethyl- and fluoroethylesters against carboxylesterases in vitro: there is no difference

Author(s)

Lukas Nics, Daniela Häusler, Wolfgang Wadsak, Karl-Heinz Wagner, Robert Dudczak, Kurt Kletter, Markus Mitterhauser

Abstract

Introduction: Carboxylesterases (CES) play a very important role in the hydrophilic biotransformation of a huge number of structurally diverse drugs and especially play a leading part in the catabolic pathway of carboxylesters or thioesters. Hence, the aim of the present study was the comparison of the in vitro stability of methyl- and ethylesters with fluoroethylesters.

Methods: We incubated methyl 3 beta-(4-iodophenyl)tropane-2 beta-carboxylate (beta-CIT)/2-fluoroethyl 3 beta-(4-iodophenyl)tropane-2 beta-carboxylate (FE@CIT), methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MTO)/ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (ETO)/2-fluoroethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (FETO), ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo [1,5-a]-[1,4]diazepine-3-carboxylate (FMZ)/2-fluoroethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a]-[1,4]diazepine-3-carboxylate (FFMZ), methyl 1-phenylethyl-4-(N-propanoylanilino)piperidine-4-carboxylate (CFN)/2-fluoroethyl 1-phenylethyl-4-(N-propanoylanilino)piperidine-4-carboxylate (FE@CFN) and methyl 2,4-diethyl-3-methylsulfanylcarbonyl-6-phenylpyridine-5-carboxylate [(Me)(2)@SUPPY]/2-fluorethyl 2,4-diethyl-3-ethylsulfanylcarbonyl-6-phenylpyridine-5-carboxylate (FE@SUPPY) under physiological conditions. The enzymatic reactions were stopped at different time points and analyzed by a standard protocol.

Results: The Michaelis-Menten constants (K-M) and limiting velocities (V-max) are comparable. The statistical K-M values were as follows: beta-CIT/FE@CIT, P>.05; MTO/FETO, P>.06; ETO/FETO, P>.09; FMZ/FFMZ, P>.05; CFN/FE@CFN, P>.9; (Me)(2)@SUPPY/FE@SUPPY, P>.07.

Conclusion: We found no statistical difference in stability against CES in vitro. These findings support the strategy to translate C-11-methyl-/ethylesters into their longer-lived F-18-fluoroethyl analogues.

Organisation(s)

Department of Nutritional Sciences, Department of Inorganic Chemistry

External organisation(s)

Medizinische Universität Wien

Journal

Nuclear Medicine and Biology

Volume

Pages

13-17

No. of pages

ISSN

0969-8051

Publication date

2011

Peer reviewed

Yes

Austrian Fields of Science 2012

302054 Nuclear medicine, 104003 Inorganic chemistry

Portal url

https://ucrisportal.univie.ac.at/en/publications/a9e6ab8c-c87e-4ec3-8e05-d1032a77230b