Binding and hydrolysis of meperidine by human liver carboxylesterase hCE-1.
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 Ki 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 Km of hCE-1 for meperidine was 1.9 mM and the kcat (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.
Zhang
J
J
Department of Biochemistry and Molecular Biology and of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Burnell
J C
JC
Dumaual
N
N
Bosron
W F
WF
D000701:Analgesics, Opioid / Q000378:metabolism*; D001711:Biotransformation; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D011431:Dextropropoxyphene / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008614:Meperidine / Q000378:metabolism*
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008614:Meperidine; D002265:Carboxylic Ester Hydrolases; D011431:Dextropropoxyphene