Species differences in the hydrolysis of meperidine and its inhibition by organophosphate compounds.
The hydrolysis of meperidine was assayed in washed, unfortified liver microsomal fractions of guinea pig, rat, mouse, dog, and human, by following substrate disappearance as quantitated by high-performance liquid chromatography. Using the method of Lineweaver-Burk plots, the velocity of the meperidine hydrolysis reaction was not detectable in guinea pig, very low in human, and extremely high in dog. Hydrolysis of p-nitrophenyl acetate was also monitored in liver microsomal preparations from the same animal species, with guinea pig showing greatest hydrolytic activity and rat showing least hydrolytic activity for this substrate. The data in the above two assays suggested that meperidine hydrolysis is mediated by a unique esterase not present in guinea pig and very low in human, but present with high activity in dog liver microsomes. From these comparative studies we concluded that liver microsomes from different species may contain different carboxylesterases having different affinities for meperidine. To further characterize meperidine carboxylesterase of dog and rat liver microsomes, inhibitory studies in vitro with two organophosphate compounds--paraoxon (diethyl-p-nitrophenyl phosphate) and soman (pinacolyl methylphosphonofluoridate)--indicated a varied pattern of enzyme inhibition. These results suggested that liver microsomal carboxylesterases are involved in the metabolism of meperidine and that interference with these enzymes by organophosphate compounds may alter pharmacologic and toxicologic effects of meperidine.
Luttrell
W E
WE
Department of Pharmacology, Eastern Virginia Medical School, Norfolk 23501.
Castle
M C
MC
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D008614:Meperidine / Q000378:metabolism* / Q000493:pharmacokinetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013997:Time Factors
D009943:Organophosphorus Compounds; D011506:Proteins; D008614:Meperidine; D002265:Carboxylic Ester Hydrolases