The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

Abstract

Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates and thioesters, and bioconverting prodrugs and soft drugs. Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human intestine only expresses CES2. The unique tissue distribution of CES enzymes provides great opportunities to design prodrugs or soft drugs for tissue targeting. CES enzymes have moderate to high inter-individual variability and exhibit low to no expression in the fetus, but increase substantially during the first few months of life. The CES genes are highly polymorphic and some CES genetic variants show significant influence on metabolism and clinical outcome of certain drugs. Marked species differences in tissue distribution and catalytic activity have been observed for CES enzymes. Careful evaluation is required when selecting animal models for human translation. Monkeys appear to be more predictive of human pharmacokinetics than other species for CES substrates. In vitro - in vivo extrapolation of clearance is still in its infancy for CES enzymes and further exploration is needed. CES enzymes are moderately inducible through a number of transcription factors and can be repressed by inflammatory cytokines. Low risk of clinical drug-drug interaction is anticipated for CES, although they should not be overlooked, particularly interaction with alcohols. In vitro and in vivo tools are continuously being developed to characterize CES substrates and inhibitors.

Metabolite Profiling and Distribution of Militarine in Rats Using UPLC-Q-TOF-MS/MS

“…Both phases I and II reactions were involved in militarine metabolism, whereas hydrolysis was the dominant metabolic pathway. As a common ester, militarine was converted to gymnoside I and II, gastrodin, and isobutyl-malic acid by carboxylesterase [33]. Then, these primary hydrolytic metabolites could proceed further biological metabolism include hydrolyzation, oxidation, and conjugation.…”

Targeting of Perforin Inhibitor into the Brain Parenchyma Via a Prodrug Approach Can Decrease Oxidative Stress and Neuroinflammation and Improve Cell Survival

“…In these cell homogenates, the half-lives of PFI-PD were approximately 4-6 h. Unfortunately, the other subtypes of the CES family and their localization within the brain are still poorly understood. Furthermore, when designing prodrugs to be bioconverted via CESes, it is essential to take into account the high expression of CES1 in the liver and CES2 in the intestine [69]. Moreover, when studying the prodrugs, the species differences should be acknowledged, e.g., due to the different expression profiles of human and rodent bioconverting enzymes throughout the body, it is difficult to make reliable correlations between these species [51,70].…”

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

“…The rate of metabolite formation from the probe substrate is quantitatively determined. For other membrane bound non‐CYP enzymes, HLM or human liver S9 may be used in inhibition studies, e.g., carboxylesterases (CESs) (Di, ; Di, ), whereas human liver cytosol or S9 are used for studying soluble enzymes, e.g., aldehyde oxidase (AO) (Dalvie & Di, ; Di, ; Zientek, Jiang, Youdim, & Obach, ).…”