Cholinesterases tissue distribution

Tomokuni K, Hasegawa T, Hirai Y, et al. 1985. The tissue distribution of diazinon and the inhibition of blood cholinesterase activities in rats and mice receiving a single intraperitoneal dose of diazinon. Toxicology 37(l-2) 91-98. 

An understanding of the metabolism of local anesthetics is important in clinical practice, because the overall toxicity of a drug depends not only on its uptake and tissue distribution but also on how it is deactivated in vivo. The amino ester-type local anesthetics are rapidly hydrolyzed by plasma cholinesterase (also known as pseudocholinesterase), which is widely distributed in body tissues. These compounds can therefore be metabolized in the blood, kidneys, and liver and, to a lesser extent, at the site of administration. For example, both procaine and benzocaine are easily hydrolyzed by cholinesterase into PABA and the corresponding N,N -diethylaminoethyl alcohol. 

Cholinesterases are widely distributed throughout the body in both neuronal and non-neuronal tissues 195... 

Cholinesterases are widely distributed throughout the body in both neuronal and non-neuronal tissues. Based largely on substrate specificity, the cholinesterases are subdivided into the acetylcholinesterases (AChEs) (EC... 

It is well established that acetylcholine can be catabolized by both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) these are also known as "true" and "pseudo" cholinesterase, respectively. Such enzymes may be differentiated by their specificity for different choline esters and by their susceptibility to different antagonists. They also differ in their anatomical distribution, with AChE being associated with nervous tissue while BChE is largely found in non-nervous tissue. In the brain there does not seem to be a good correlation between the distribution of cholinergic terminals and the presence of AChE, choline acetyltransferase having been found to be a better marker of such terminals. An assessment of cholinesterase activity can be made by examining red blood cells, which contain only AChE, and plasma. 

In the clinic, esmolol s distribution half-life is 2 min and its elimination half-life is 9 min. Esmolol hydrochloride is rapidly metabolized by hydrolysis of the ester linkage, chiefly by esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase [22]. Its volume of distribution is 3.4 L kg-1, and its total clearance is 285 mL kg-1 min-1, "... which is greater than cardiac output thus the metabolism ofesmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flout [22]. As expected from such a "... high rate of blood-based metabolism, less than 2% of the drug is excreted unchanged in the wind [22]. Within 24 h after infusion, approximately... 

Echothiophate iodide is a long-lasting cholinesterase inhibitor of the irreversible type, as is isofluorphate. Unlike the latter, however, it is a quaternary salt, and when applied locally, its distribution in tissues is limited, which can be very de.sirablc. It is used as a long-acting anticholinesterase agent in the treatment of glaucoma. 

Model refinement and validation for both the chltnpyrifos and the diazinon PBPK/PD models wa.s accomplished by conducting a scries of in vivo pharmacokinetic and pharmacodynamic studies in the rat and by evaluating the capability of the model to accurately simulate in vivo data published in the literature. The experimental details are fully described in Timchalk et ai (2002b) and Poet et at. (2004). In brief, these studies involved an acute oral exposure to chlorpyrifos or diazinon and the blood time course of the parent compounds and metabolites was determined, as well as the time course for the cholinesterase inhibition in several tissues. Representative results and model simulations are presented in Fig. 12 and 13 for the pharmacokinetic and pharmacodynamic response in rats following comparable oral doses (50 and 100 mg/kg) of chlorpyrifos and diazinon, respectively, The overall response was fairly comparable for these two insecticides, and the models reasonably simulated both dosimetry and the dose-dependent cholinesterase inhibition. These results arc very consistent with a fairly rapid oral absorption for both insecticides and subsequent metabolism and distribution of the active oxon metabolites. Figure 14 illustrates the capability of the diazinon PBPK/PD model to simulate rodent dosimetry data from the open literature and the capability of the model to accommodate alternative exposure routes (Poet et ai, 2004). In these examples, the time course of diazinon in plasma and cholinesterase inhibition in tissues (i.e.. blood,... 

There are many cholinesterase inhibitors diminishing both AChE and BuChE activities to a comparable extent. However, there are a number of important exceptions the selectivity of some OP and carbamates for BuChE has been described by Aldridge (A4). Carbamates belong to a group of insecticides having a large variation in their effectiveness. They are biologically active because of their structural complementarity to the active surface of AChE and their consequent reaction as substrates with very low turnover numbers (A4, B2). Some carbamates inhibit selectively either AChE or BuChE (Bll, B22). The toxicity of carbamates is dependent on their ability to carbamylate AChE in different tissues and on other factors such as distribution, detoxification, and metabolization. 

Isoenzymes are enzyme variants found in all members of a species and their occurrence and distribution depend on such factors as the phase of development, the tissue in question and sometimes even the season of the year. The latter is instanced by the rainbow trout which produces summer and winter forms of brain cholinesterase while, at intermediate temperatures, both forms are produced. 

One of the pillars upon which rests the prevailing theory of the chemical mediation of nerve impulses is the uniqueness, in conducting tissue, of the enzyme that hydrolyzes acetylcholine. The characteristics of acetylcholinesterase that distinguish it from the other cholinesterases are as follows (1) A small Km when acetylcholine is the substrate. (2) Inhibition of the hydrolysis of acetylcholine by the substrate so that when the velocity is plotted against substrate concentration a bell-shaped curve results. (3) A rate of hydrolysis that is greatest with acetylcholine, less with propionylcholine, and the least with butyrylcholine. None of these properties is shared by the other cholinesterases. Acetylcholinesterase occurs, however, not only in conducting tissue but also in erythrocytes and cobra venom. The distribution of cholinesterases has been reviewed by Augustinsson. ... 

In summary, DFP is rapidly distributed, boimd to tissues in the form of the bound diisopropryl phospho-ryl group to proteins, released as metabolite (DIP), and finally excreted, mainly in the urine. There is evidence that a high proportion of binding is to other sites different from cholinesterases. Moreover, the time course of CNS effects suggests that other noncholinesterase interactions are involved in DFP neurotoxicity. 

Analysis of tissues of monkeys and rodents [369] sacrificed some days after administering Pb(C2H5)4 showed lead widely distributed in soft tissue with an excess In the liver but not in the brain. Following injection, enhanced lead concentrations were also found in bone [369]. No significant reduction in cholinesterase activity on addition of Pb(C2H5)4 to various enzyme sources is observed in vitro. Transient cholinesterase inhibition found in in vivo experiments with rhesus monkeys is considered to be biologically insignificant [368]. 

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