Binding and Hydrolysis of Meperidine by Human Liver Carboxylesterase hCE-1

• Published in: The Journal of pharmacology and experimental therapeutics 1999-07, Vol.290 (1), p.314-318
• Main Authors: Zhang, J, Burnell, J C, Dumaual, N, Bosron, W F
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - metabolism; Biotransformation; Carboxylic Ester Hydrolases - metabolism; Chromatography, High Pressure Liquid; Dextropropoxyphene - metabolism; Enzyme Inhibitors - pharmacology; Gas Chromatography-Mass Spectrometry; Half-Life; Humans; Hydrolysis; In Vitro Techniques; Isoenzymes - metabolism; Kinetics; Liver - enzymology; Liver - metabolism; Meperidine - metabolism
• ISSN: 0022-3565; 1521-0103

Human liver carboxylesterases catalyze the hydrolysis of apolar drug or xenobiotic esters into more soluble acid and alcohol products for elimination. Two carboxylesterases, hCE-1 and hCE-2, have been purified and characterized with respect to their role in cocaine and heroin hydrolysis. The binding of meperidine (Demerol) and propoxyphene (Darvon) was examined in a competitive binding, spectrophotometric assay. The hCE-1 and hCE-2 bound both drugs, with K i values in the 0.4- to 1.3-mM range. Meperidine was hydrolyzed to meperidinic acid and ethanol by hCE-1 but not hCE-2. The K m of hCE-1 for meperidine was 1.9 mM and the k cat (catalytic rate constant) was 0.67 min −1 . Hydrolysis of meperidine by hCE-1 was consistent with its specificity for hydrolysis of esters containing simple aliphatic alcohol substituents. Hence, hCE-1 in human liver microsomes may play an important role in meperidine elimination. Propoxyphene was not hydrolyzed by hCE-1 or hCE-2. This observation is consistent with the absence of a major hydrolytic pathway for propoxyphene metabolism in humans.