Drug metabolism carboxylesterases

Imai, T. (2006) Human carboxylesterase isozymes catalytic properties and rational drug design. Drug Metabolism and Pharmacokinetics, 21, 173-185. 

Redinbo, M., Bencharit, S. and Potters, P. (2003), Human carboxylesterase 1 from drug metabolism to drug discovery, Biochem. Soc. Trans., 31, 620-624. 

Carboxylesterases and amidases catalyze hydrolysis of carboxy esters and carboxy amides to the corresponding carboxylic acids and alcohols or amines. In general those enzymes capable of catalyzing hydrolysis of carboxy esters are also amidases, and vice versa (110). The role of these enzymes in metabolsim of drugs and insecticides has been reviewed (111, 112). In addition to the interest in mammalian metabolism of drugs and environmental chemicals, microbial esterases have been used for enantioselective hydrolyses (113, 114). 

The nasal route of drug delivery avoids the liver first-pass effect, but the pseudo-first-pass effect owing to nasal metabolism of drugs is still a concern. Many enzymes such as carboxylesterase, aldehyde dehydrogenase, glutathione transferases, UDP-glucoronyl transferase, epoxide hydrolases, CYP-dependent monoxygenases, exo- and endopeptidases and proteases are present in the nasal mucosa.106 108,110,116 CYP enzymes are present abundantly in the olfactory epithelium.107,110... 

Figure 13.44. Metabolic activation of capecitabine (50), a site-selective multistep prodrug of the antitumor drug 5-fluorouracil (5-FU) (53)Following oral absorption, the prodrug is hydrolyzed by liver carboxylesterase to a carbamic acid that spontaneously decarboxylates to 5 -deow-5-fluorocy-tidine (51). The latter is transformed into 5 -deoxy-5-fluorouridine (52) by cytidine deaminase present in the liver and tumors. The third activation step occurs selectively in tumor cells and involves the transformation to 5-FU (53), catalyzed by thymidine phosphorylase (221).

The carboxylesterase superfamily catalyzes the hydrolysis of ester- and amide-containing compounds. These enzymes are found in both the ER and cytosol of many cell types and are involved in detoxification or metabolic activation of drugs, environmental toxins, and carcinogens. Car-boxylesterases also catalyze the activation of prodrugs to their respective free acids. For example, the prodrug and cancer chemotherapeutic agent irinotecan is bioactivated by plasma and intracellular carboxylesterases to the potent topoisomerase inhibitor SN-38. 

Interestingly, imidazoles were found as the inhibitors of carboxylesterases, which could relate in the metabolism of esterified drugs and xenobiotics [45],... 

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