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

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• 作者：Lukas Nics^a ; ^b ; Daniela Haeusler^a ; ^c ; Wolfgang Wadsak^a ; ^d ; Karl-Heinz Wagner^b ; Robert Dudczak^a ; Kurt Kletter^a ; Markus Mitterhauser^a ; ^c ; ^e ; ^{markus.mitterhauser@meduniwien.ac.at}
• 关键词：Metabolism ; Michaelis– ; Menten kinetics ; In vitro ; Carboxylesterase (CES) ; EC 3.1.1.1
• 刊名：Nuclear Medicine and Biology
• 出版年：2011
• 出版时间：January 2011
• 年：2011
• 卷：38
• 期：1
• 页码：13-17
• 全文大小：450 K

文摘

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.