Allosteric kinetics of human carboxylesterase 1: Species differences and interindividual variability

Esterified drugs such as imidapril, derapril, and oxybutynin hydrolyzed by carboxylesterase 1 (CES1) are extensively used in clinical practice. The kinetics using the CES1 substrates have not fully clarified, especially concerning species and tissue differences. In the present study, we performed the kinetic analyses in humans and rats in order to clarify these differences. The imidaprilat formation from imidapril exhibited sigmoidal kinetics in human liver microsomes (HLM) and cytosol (HLC) but Michaelis‐Menten kinetics in rat liver microsomes and cytosol. The 2‐cyclohexyl‐2‐phenylglycolic acid (CPGA) formation from oxybutynin were not detected in enzyme sources from rats, although HLM showed high activity. The kinetics were clarified to be different among species, tissues, and preparations. In individual HLM and HLC, there was large interindividual variability in imidaprilat (31‐ and 24‐fold) and CPGA formations (15‐ and 9‐fold). Imidaprilat formations exhibited Michaelis‐Menten kinetics in HLM and HLC with high activity but sigmoidal kinetics in those with low activity. CPGA formations showed sigmoidal kinetics in high activity HLM but Michaelis‐Menten kinetics in HLM with low activity. We revealed that the kinetics were different between individuals. These results could be useful for understanding interindividual variability and for the development of oral prodrugs. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5434-5445, 2008