Intestinal esterases

Drugs may also undergo hydrolysis by intestinal esterases (hydrolases), more specifically carboxylesterases (EC 3.1.1.1) in the intestinal lumen and at the brush border membrane [58, 59]. It has been shown that intestinal hydrolase activity in humans was closer to that of the rat than the dog or Caco-2 cells [60]. In these studies, six propranolol ester prodrugs and p-nitrophenylacetate were used as substrates, and the hydrolase activity found was ranked in the order human > rat Caco-2 cells > dog for intestinal microsomes. The rank order in hydrolase activity for the intestinal cytosolic fraction was rat > Caco-2 cells = human > dog. The hydrolase activity towards p-nitrophenylacetate and tenofovir disoproxil has also been reported in various intestinal segments from rats, pigs and humans. The enzyme activity in intestinal homogenates was found to be both site-specific (duodenum > jejunum > ileum > colon) and species-dependent (rat > man > Pig)-... 

M., Sugiura, M., Species difference and characterization of intestinal esterase on the hydrolyzing activity of ester-type drugs, Jpn. J. Pharmacol. 

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],... 

Cefditoren pivoxil (12 Spectracef TAP Pharmaceuticals, 2001) is an oral prodrug of cefditoren (13), a derivative of cephalosporin isolated from Cephalosporium species. The prodrug is readily hydrolyzed by intestinal esterases to the microbiologically active cephalosporin cefditoren (13)... 

White RD, Earnest DL, Carter DE The effect of intestinal esterase inhibition on the in vivo absorption and toxicity of di- -butyl phthalate. Food Chem Toxicol 21 99-101, 1983... 

Intestinal esterase activity. Oil was administered to rats at different doses with or without clofibrate for 15 days. The hypolipidemic action of clofibrate was not influenced by the amount of fat. Clofibrate did not affect lower cholesterol concentration... 

Inoue, M., Morikawa, M., Tsuboi, M. and Sugiura, M. (1979) Studies of human intestinal esterase. IV. Application to the development of ester prodrugs of salicylic acid. Journal of Pharmacohio-Dynamics, 2, 229-236. 

A logical extension of this type of study, because of the natural presence of bile salts in the intestine and the presence of synthetic surfactants in formulations, is the consideration of bile salt-surfactant mixtures. One such study [118] has considered the effect of sodium glycocholate and its mixtures with NaLS and polysorbate 80 on the absorption and metabolism of a thiamine disulphide derivative, in rats (see Scheme 7.1). It had previously been shown that surfactants altered the reaction rates of the thiol-disulphide exchange reaction that these compounds undergo [119] and that o-benzoyl thiamine disulphide interacts with the lauryl sulphate anion to form a 1 2 complex this complex is broken up by sodium glycocholate to form new mixed micelles of thiamine derivatives and the surfactants. NaLS decreases /c and /c promoting the conversion of V to VII. The reduction in absorption and the decreased enzymatic deacylation are both explained by complex formation, although inactivation of intestinal esterase by... 

For a series of esters of propranolol, esterases from different tissues displayed varying rates of hydrolysis towards esters of the R and S forms of the drug. Plasma esterases hydrolysed the R esters at about ten times the rate of the S esters, where the rate of hydrolysis was rapid (Table 5.6). In the case of the hindered piva-late ester the rate of hydrolysis was much slower and the chiral discrimination was much reduced. Chiral discrimination by liver and intestinal esterases favoured hydrolysis of the S esters but was less marked, reflecting... 

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