Butyrylcholinesterase half-life

After release from the presynaptic terminal, acetylcholine molecules may bind to and activate an acetylcholine receptor (cholinoceptor). Eventually (and usually very rapidly), all of the acetylcholine released will diffuse within range of an acetylcholinesterase (AChE) molecule. AChE very efficiently splits acetylcholine into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter (Figure 6-3). Most cholinergic synapses are richly supplied with acetylcholinesterase the half-life of acetylcholine in the synapse is therefore very short. Acetylcholinesterase is also found in other tissues, eg, red blood cells. (Another cholinesterase with a lower specificity for acetylcholine, butyrylcholinesterase [pseudocholinesterase], is found in blood plasma, liver, glia, and many other tissues.)... 

Duysen, E.G., Bartels, C.F. and Lockridge, O. Wild-type and A328W mutant human butyrylcholinesterase tetramers expressed in Chinese hamster ovary cells have a 16-hour half-life in the circulation and protect mice from cocaine toxicity, J. Pharmacol. Exp. Ther., 302, 751, 2002. 

Tacrine, an aminoacridine synthesized in the 1930s, is a nonclassic cholinesterase inhibitor that binds to both AChE or butyrylcholinesterase (46). It was approved in 1993 for the treatment of AD. Approximately 20% of tacrine-treated patients may show improvement, but its use has been limited because of hepatotoxicity. Use of tacrine has greatly decreased because of the recent development of safer AChEls. Tacrine is extensively metabolized by CYP450 to at least three metabolites. The major metabolite, 1-hydroxy-tacrihe, is active. Its elimination half-life is between 1.5 and 4 hours, with metabolites being are excreted via the urine. 

Donepezil is another "nonclassic," centrally acting, reversible, noncompetitive AChEI that was approved in 1997 for treatment of mild-to-moderate AD and dementia. Its selectivity for AChE is 570- to 1,250-fold that for butyrylcholinesterase, and it also exhibits greater affinity for brain AChE than for AChE in the periphery (47). When compared to tacrine, donepezil exhibits greater CNS AChE selectivity, longer elimination half-life (70-104 hours in subjects older than 55 years) and little or no potential for hepatotoxicity. Donepezil is metabolized by CYP2D6 and CYP3A4 via demethylation, debenzylation, hydroxylation, oxidation to the c/s-N-oxide, and glucuronidation. The 6-0-desmethyl metabolite accounts for 11 % of a dose, and it exhibits AChE inhibitory activity comparable to that of the parent compound. 

Analytical procedures applied to diagnosis and retrospective verification of exposure to OP include (Worek et al., 2005) (i) biochemical determination of ChE activity (ii) identification of imbound OP (iii) identification of decomposition products (iv) fluoride-induced reactivation of inhibited ChE, followed by analysis of the inhibitor and (v) analysis of phosphyl-protein-adducts after tryptic digestion of the protein. The last procedure is regarded to be the most specific and sensitive, but it has the drawback of being strongly dependent on the analysis of butyrylcholinesterase (BChE), the most abim-dant plasma serine esterase with a half-life of about 16 days. 

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