Small intestinal esterase activity

Carboxylesterases (EC 3.1.1.1) can be detected in most mammalian tissues. Besides organs with high carboxylesterase activity such as liver, kidney, and small intestine, esterase activity is present, e.g., in the brain, nasal mucosa, lung, testicle, and saliva. Compared to rat plasma, human plasma contains little carboxylesterase, its esterase activity being essentially due to cholinesterase [61][73][79][89-91],... 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

It was reported that the distribution and activities of esterases that catalyze pyrethroid metabolism using several human and rat tissues, including small intestine, liver, and serum, were examined [30]. The major esterase in human intestine was hCE2. //c/n.v-Permethrin was effectively hydrolyzed by pooled human intestinal microsomes (five individuals), while deltamethrin and bioresmethrin were not. This result correlated well with the substrate specificity of recombinant hCE2. In contrast, pooled rat intestinal microsomes (five animals) hydrolyzed trans-permethrin 4.5 times slower than the human intestinal microsomes. Furthermore, pooled samples of cytosol from human or rat liver were ca. half as hydrolytically active as the corresponding microsome fraction toward pyrethroids however, the cytosolic fractions had significant amounts (ca. 40%) of the total hydrolytic activity. Moreover, a sixfold interindividual variation in hCEl protein expression in human hepatic cytosols was observed. 

The intracellular localization of carboxylesterases is predominantly microsomal, the esterases being localized in the endoplasmic reticulum [73] [79] [93], They are either free in the lumen or loosely bound to the inner aspect of the membrane. The carboxylesterases in liver mitochondria are essentially identical to those of the microsomal fraction. In contrast, carboxylesterases of liver lysosomes are different, their isoelectric point being in the acidic range. Carboxylesterase activity is also found in the cytosolic fraction of liver and kidney. It has been suggested that cytosolic carboxylesterases are mere contaminants of the microsomal enzymes, but there is evidence that soluble esterases do not necessarily originate from the endoplasmic reticulum [94], In guinea pig liver, a specific cytosolic esterase has been identified that is capable of hydrolyzing acetylsalicylate and that differs from the microsomal enzyme. Also, microsomal and cytosolic enzymes have different electrophoretic properties [77]. Cytosolic and microsomal esterases in rat small intestinal mucosa are clearly different enzymes, since they hydrolyze rac-oxazepam acetate with opposite enantioselectivity [95], Consequently, studies of hydrolysis in hepatocytes reflect more closely the in vivo hepatic hydrolysis than subcellular fractions, since cytosolic and microsomal esterases can act in parallel. 

Metabolic reactions in the liver and the small intestine are well documented. However, only sparse information is available on drug metabolism in the colon. Drug metabolism in the colon can be brought about by the host enzymes in the epithelial cells or by the microbial enzymes in the gut flora. Metabolic activities in the wall of the colon can be attributed to cytochrome P450, esterases, amidases, and various trans-ferases. Reductive drug metabolism does not appear to be important at this site. 

The wide distribution of esterase activity in the mucosa of stomach, small intestine, and colon has been exploited in designing numerous ester prodrugs [97-101]. Examples of successful ester prodrugs hydrolyzed, at least in part, in the gastrointestinal mucosa are ramipril [102], simvastatin [103], and bacampicillin [104]. 

Whereas many cephalosporins such as cefaclor, cefadroxil, cefonicid, ceforanide, ceftazidime, cefti-zoxime, cefuroxime, cephalexin, and cephradine are not metabolized, cefamandole naftate is rapidly hydrolyzed in plasma to cefamandole, which has greater antibacterial activity than the parent compound. Ceftriaxone is metabolized to a small extent to micro-biologically inactive metabolites in the intestines after biliary excretion. Cefuroxime axetil is rapidly hydrolyzed to cefuroxime, the microbiologically active form of the drug, by nonspecific esterases in the intestinal mucosa and blood following oral administration. The axetil moiety is further metabolized to acetaldehyde and acetic acid [93]. 

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