Binding and hydrolysis of meperidine by human liver carboxylesterase hCE-1

Human liver carboxylesterases catalyze the hydrolysis of apolar drug or xen obiotic esters into more soluble acid and alcohol products for elimination. Two carboxylesterases, hCE-1 and hCE-2, have been purified and characteriz ed with respect to their role in cocaine and heroin hydrolysis. The binding of meperidine (Demerol) and propoxyphene (Darvon) was examined in a compet itive binding, spectrophotometric assay. The hCE-1 and hCE-2 bound both dru gs, 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 K-m, of hCE-1 for meperidine was 1.9 mM and the k(cat) (catalytic rate constant) was 0.67 mi n-l. 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 meperi dine elimination. Propoxyphene was not hydrolyzed by hCE-1 or hCE-2. This o bservation is consistent with the absence of a major hydrolytic pathway for propoxyphene metabolism in humans.