Clinical Significance of Esterases in Man

Abstract

Esterases, hydrolases which split ester bonds, hydrolyse a number of compounds used as drugs in humans. The enzymes involved are classified broadly as cholinesterases (including acetylcholinesterase), carboxylesterases, and arylesterases, but apart from acetylcholinesterase, their biological function is unknown. The acetylcholinesterase present in nerve endings involved in neurotransmission is inhibited by anticholinesterase drugs, e.g. neostigmine, and by organophosphorous compounds (mainly insecticides). Cholinesterases are primarily involved in drug hydrolysis in the plasma, arylesterases in the plasma and red blood cells, and carboxylesterases in the liver, gut and other tissues. The esterases exhibit specificities for certain substrates and inhibitors but a drug is often hydrolysed by more than one esterase at different sites. Aspirin (acetylsalicylic acid), for example, is hydrolysed to salicylate by carboxylesterases in the liver during the first-pass. Only 60% of an oral dose reaches the systemic circulation where it is hydrolysed by plasma cholinesterases and albumin and red blood cell arylesterases. Thus, the concentration of aspirin relative to salicylate in the circulation may be affected by individual variation in esterase levels and the relative roles of the different esterases, and this may influence the overall pharmacological effect. Other drugs have been less extensively investigated than aspirin and these include heroin (diacetylmorphine), suxamethonium (succinylcholine), clofibrate, carbimazole, procaine and other local anaesthetics. Ester prodrugs are widely used to improve absorption of drugs and in depot preparations. The active drug is released by hydrolysis by tissue carboxylesterases. Individual differences in esterase activity may be genetically determined, as is the case with atypical cholinesterases and the polymorphic distribution of serum paraoxonase and red blood cell esterase D. Disease states may also alter esterase activity.

Butyrylcholinesterase and Erythrocyte Sulfhydryl-dependent Enzyme Hydrolyze Gabexate in Human Blood

“…Butyrylcholinesterase is a wellknown plasma esterase and plays an important role in drug metabolism in the blood. 18) In this study, the GB hydrolysis catalyzed by human plasma was partially suppressed by ethopropazine (Fig. 4).…”

Esterase Inhibition Attribute of Grapefruit Juice Leading to a New Drug Interaction

“…For the first time, to our knowledge, we demonstrate in this study that GFJ also inhibits esterase activity in vitro in rats and humans and in vivo in rats. Esterases, including carboxylesterases, are ubiquitous enzymes responsible for the metabolism of xeno-and endobiotics (Williams et al, 1985). Although other fruit juices are shown to inhibit esterase activity, the literature lacks reports on esterase inhibition by GFJ.…”

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

“…They were selected, as was their final concentration in the assay, based on the literature: edetic acid (EDTA) and chloromercuribenzoate (1 mM and 100 M, respectively; in-hibitors of A-esterases), paraoxon, physostigmine, metoclopramide, sodium fluoride (NaF), and bis-pnitrophenyl phosphate (BNPP) (all at 100 M; inhibitors of B-esterases), acetazolamide (100 M, inhibitor of carboxylanhydrase), and acetylsalicylic acid (100 M; aspecific inhibitor of esterases) (18)(19)(20)(21)(22)(23). Incubation mixtures contained whole blood (980 l), 700 M LEV (added as 10 l in water), and the inhibitor (added as 10 l in either water or methanol).…”