Drug‐Metabolism Enzymes and Transporter Activities as Risk Factors of Selected Marketed Drugs Associated with Drug‐Induced Fatalities

Li, Albert P.

doi:10.1002/9781119171003.ch3

Cited by 1 publication

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“…The main route of drug clearance, hepatic metabolism, is extensively studied (Zhang and Tang, 2018;Li, 2021) whereas ocular drug metabolism is poorly understood (Dumouchel et al, 2018). The eye can be directly exposed by administered compounds; however, the role of local metabolism (del Amo et al, 2017;Dumouchel et al, 2018) is unclear although it may to some extent prevent accumulation of xenobiotics (Duvvuri et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Activity and Expression of Carboxylesterases and Arylacetamide Deacetylase in Human Ocular Tissues

et al. 2022

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As a multi-tissue organ, the eye possesses unique anatomy and physiology including differential expression of drug-metabolizing enzymes. Several hydrolytic enzymes, that play a major role in drug metabolism and bioactivation of prodrugs, have been detected in ocular tissues but data on their quantitative expression is scarce. Also, many ophthalmic drugs are prone to hydrolysis. Metabolic characterization of individual ocular tissues is useful for the drug development process, and therefore, seven individual ocular tissues from human eyes were analyzed for the activity and expression of carboxylesterases (CESs) and arylacetamide deacetylase (AADAC). Generic and selective human esterase substrates 4-nitrophenyl acetate (most esterases), D-luciferin methyl ester (CES1), fluorescein diacetate and procaine (CES2), and phenacetin (AADAC) were applied to determine the enzymes' specific activities.Enzyme kinetics and inhibition studies were performed with isoform-selective inhibitors digitonin (CES1) and verapamil and diltiazem (CES2). Enzyme contents were determined using quantitative targeted proteomics, and CES2 expression was confirmed by Western blotting. The expression and activity of human CES1 among ocular tissues varied by >10fold, with the highest levels found in the retina and iris-ciliary body. In contrast, human CES2 expression appeared lower and more similar between tissues whereas AADAC could not be detected. Inhibition studies showed that hydrolysis of fluorescein diacetate is also catalyzed by enzymes other than CES2. This study provides, for the first time, quantitative information on the tissue-dependent expression of human ocular esterases which can be useful for the development of ocular drugs, prodrugs, and in pharmacokinetic modeling of the eye.

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