Hepatic enzymes cholinesterase

Solberg and co-workers have applied discriminate analysis of clinical laboratory tests combined with careful clinical and anatomic diagnoses of liver disease in order to determine which combinations of the many dozen liver diagnostic tests available are the bes t ( ). These authors found that the measurement of GPT, GMT, GOT, ALP and ceruloplasmin were the most useful enzymatic tests, when combined with other non-enzymatic tests such as the measurement of bilirubin, cholesterol, hepatitis-B associated Australian antigen, etc. Another group of highly useful enzymes, not discussed in this review, are those clotting factors and the enzyme cholinesterase which are synthesized by the liver cells. 

Most of the hemiesters 8.136 underwent no or little enzymatic degradation in human plasma, in agreement with the known inertness of hemiesters toward cholinesterase (see Chapt. 7). In contrast, very rapid hydrolysis was usually seen in pig and rat liver preparations, indicating the involvement of carboxylesterases. The only inert compound was the 3,3-dimethylglutarate hemiester of paracetamol (8.136, X = C(CH3)2CH2, Fig. 8.12). Data on the hydrolysis of such prodrugs by human hepatic enzymes will be welcome. 

Local anesthetics are usually eliminated by hydrolyzing or breaking apart the drug molecule. This metabolic hydrolysis is catalyzed by hepatic enzymes or enzymes circulating in the plasma (e.g., the plasma cholinesterase). Once metabolized, the kidneys excrete the polar drug metabolites. 

Some of the common local anesthetics e.g., tetracaine) are esters they are hydrolyzed and inactivated primarily by a plasma esterase, probably plasma cholinesterase. Hepatic enzymes also hydrolyze local anesthetic esters. Since spinal fluid contains little or no esterase, anesthesia produced by the intrathecal injection of an anesthetic agent will persist until the local anesthetic agent has been absorbed into the circulation. 

Doxacurium is a mixture of three trans, trans-stereoisomers, a dl pair [(1R, 1 R,2S,2 S) and (1S,1 S,2R,2 R)] and a meso form (1R,1 S,2S,2 R). Doxacurium is hydrophilic, has a small volume of distribution, and is distributed primarily to extracellular fluids. It is not metabolized by plasma cholinesterase or hepatic enzymes and does not undergo Hofmann elimination. 

Natural (-)-cocaine (7.57, Fig. 7.8), which has the (2/ ,3S)-configuration, is a relatively poor substrate for hepatic carboxylesterases and plasma cholinesterase (EC 3.1.1.8), and also a potent competitive inhibitor of the latter enzyme [116][121], In contrast, the unnatural enantiomer, (+)-(2S,3/ )-cocaine, is a good substrate for carboxylesterases and cholinesterase. Because hydrolysis is a route of detoxification for cocaine and its stereoisomers, such metabolic differences have a major import on their monooxygenase-catalyzed toxification, a reaction of particular effectiveness for (-)-cocaine. 

The mechanism of human toxicity has not been clearly delineated. In animal models, solanaceous alkaloids inhibit cholinesterase activity and demonstrate cardiac glycoside activity. Solanine inhibits hepatic microsomal enzymes and can cause hemolysis. 

M16. Molander, D. W., Graver, L. F., and Packs, G. T., Liver enzymes, serum glutamic oxalacetic transminase, cholinesterase and alkaline phosphatase in primary and metastatic hepatic neoplasia. Acta Unio Int. Cancrum 16, 1478-1481 (1960). 

Hydrolysis. Hydrolysis of esters and amides is a common pathway of drug metabolism. The liver microsomes contain non-specific esterases, as do other tissues and plasma. Hydrolysis of an ester results in the formation of an alcohol and an acid hydrolysis of an amide results in the formation of an amine and an acid. The ester procaine, a local anaesthetic, is rapidly hydrolysed by plasma cholinesterases and, to a lesser extent, by hepatic microsomal esterase. An example of an amide which is hydrolysed, is the antiarrhythmic drug procainamide. Enalapril, a prodrug, is hydrolysed by esterases to the active metabolite enalapri-late, which inhibits the angiotensin-converting enzyme. 

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