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

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

doi:10.1016/j.nucmedbio.2010.07.004

« Previous Next »Nuclear Medicine and Biology
Volume 38, Issue 1 , Pages 13-17, January 2011

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

Lukas Nics
- Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria
- Department of Nutritional Sciences, University of Vienna, A-1090 Vienna, Austria
Daniela Haeusler
- Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria
- Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, A-1090 Vienna, Austria
Wolfgang Wadsak
- Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria
- Department of Inorganic Chemistry, University of Vienna, A-1090 Vienna, Austria
Karl-Heinz Wagner
- Department of Nutritional Sciences, University of Vienna, A-1090 Vienna, Austria
Robert Dudczak
- Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria
Kurt Kletter
- Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria
Markus Mitterhauser
- Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria
- Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, A-1090 Vienna, Austria
- Hospital Pharmacy of the General Hospital of Vienna, A-1090 Vienna, Austria
- Corresponding author. Department of Nuclear Medicine, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +43 1 40400 1557; fax: +43 1 40400 1559.

Received 31 May 2010; received in revised form 29 June 2010; accepted 1 July 2010. published online 02 September 2010.

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 3β-(4-iodophenyl)tropane-2β-carboxylate (β-CIT)/2-fluoroethyl 3β-(4-iodophenyl)tropane-2β-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: β-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.

Keywords: Metabolism, Michaelis–Menten kinetics, In vitro, Carboxylesterase (CES), EC 3.1.1.1