The Role of Human Carboxylesterases in Drug Metabolism: Have We Overlooked Their Importance?

Abstract

Carboxylesterases are a multi-gene family of enzymes widely distributed throughout the body of mammals that catalyze the hydrolysis of esters, amides, thioesters, and carbamates. In humans, two carboxylesterases, hCE1 and hCE2, are important pathways of drug metabolism. Both are expressed in the liver, but levels of hCE1 greatly exceed those of hCE2. In the intestine only high levels of hCE2 are expressed. The most common drug substrates are ester prodrugs specifically designed to enhance oral bioavailability that must be hydrolyzed to their active carboxylic acid by hydrolysis after absorption from the gastrointestinal tract. However, carboxylesterases also play an important role in the hydrolysis of some drugs to inactive metabolites. It has been widely accepted that drugs undergoing hydrolysis by hCE1 and hCE2 are not subject to clinically significant alterations in their disposition, but there is now a significant and growing body of evidence that genetic polymorphisms, drug-drug interactions, drug-disease interactions and other factors are important determinants of the variability in the therapeutic response to carboxylesterase-substrate drugs. The implications for the safe and effective use of drug therapy is far-reaching, as the patient exposure to substrate drugs includes numerous agents from widely prescribed therapeutic classes such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, antiplatelets, HMG-CoA inhibitors, antivirals, and central nervous system agents.

Different Hydrolases Involved in Bioactivation of Prodrug-Type Angiotensin Receptor Blockers: Carboxymethylenebutenolidase and Carboxylesterase 1

“…It has often been reported that CC is converted to candesartan by carboxylesterases via intestinal and hepatic first-pass metabolism (Miwa et al, 1998;Easthope and Jarvis, 2002); however, which isozymes of CES1 or CES2 are a major contributor remained unknown until now. Although Laizure et al (2013) supposed that CC is a CES2 substrate because of CC's large alcohol group of the prodrug moiety that CES2 prefers as a substrate, in the present study, the recombinant CES2 exhibited only low CC-hydrolase activity in contrast to rapid hydrolysis by the recombinant CES1. Moreover, the intestinal subcellular fractions showed minimal CC-hydrolase activity in all the species tested including humans, indicating negligible involvement of CES2, which had been reported to be expressed in the intestine in mice, rats, monkeys, and humans (Taketani et al, 2007;Satoh and Hosokawa, 2010).…”

In Vitro Hydrolysis and Transesterification of CDP323, an α4β1/α4β7 Integrin Antagonist Ester Prodrug

“…Although hCES1 and hCES2 have overlapping substrate recognition, clear evidence of ester-based substrate specificity has been observed (Satoh et al, 2002). In general, hCES1 accommodates substrates with a large acyl moiety whereas hCES2 favors substrates with a large alcohol substituent (Laizure et al, 2013).…”

Hepatic, Intestinal, Renal, and Plasma Hydrolysis of Prodrugs in Human, Cynomolgus Monkey, Dog, and Rat: Implications for In Vitro–In Vivo Extrapolation of Clearance of Prodrugs

“…Many prodrugs are inactive compounds with carboxyl-ester, thio-ester, or amide (Taketani et al, 2007;Laizure et al, 2013), which are subsequently hydrolyzed to an active drug; the extent of hydrolysis markedly affects the pharmacologic activity and/or toxicity of these compounds. The intentional esterification to a prodrug has been used across different classes of drugs (e.g., antivirals, angiotensin-converting enzyme inhibitors) mostly to improve drug absorption and bioavailability (Imai, 2006;Li et al, 2008).…”