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Medical Management of Chemical Warfare Agents
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
While the normal functions of BuChE and CaE in the human body are unknown, BuChE is responsible for hydrolyzing drugs that contain ester linkages. These include ester local anesthetics such as cocaine, procaine, chloroprocaine, and tetracaine; the depolarizing muscle relaxant succinylcholine; and the non-depolarizing neuromuscular blocking drug mivacurium (Jensen et al., 1995). Other drugs hydrolyzed (broken down by combining with water) by plasma cholinesterase include the short acting beta blocker esmolol, remifentanil (an opioid), the intravenous anesthetic induction drug etomidate (often used in situations of cardiovascular instability), propanidid (not available within the United States), monoamine oxidase inhibitors (anti-depression medications), and the anti-cancer medication methotrexate (Iohom et al., 2004). Human carboxylesterase 1 hydrolyzes heroin and cocaine (Redinbo et al., 2003).
S
Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Sofosbuvir is a nucleotide prodrug that is extensively metabolised. The active metabolite is formed in hepatocytes and not observed in plasma. The predominant (>90%) metabolite, GS-331007, is inactive. It is formed through sequential and parallel pathways to the formation of active metabolite. The metabolic pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A or carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide binding protein followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
Carboxylesterase Inhibitors: Relevance for Pharmaceutical Applications
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Mammalian carboxylesterases (CES, E.C. 3.1.1.1) are key members of the serine hydrolase superfamily, which are localized within the lumen of the endoplasmic reticulum (ER) in various tissues (Satoh and Hosokawa, 1998; 2006; Wang et al., 2018). As their name implies, CES catalyze the ester cleavage of a large number of structurally diverse ester- or amide-containing substrates into the corresponding alcohol/amine and carboxylic acid. Actually, CES can hydrolyze ester, thioester, amide, and carbamate linkages in a wide variety of endo- and xenobiotic compounds, thus play key roles in endobiotic metabolism, as well as in activation and detoxification of xenobiotics (Satoh and Hosokawa, 1998; Wang et al., 2018). In the human body, human carboxylesterase 1 (CES1) and human carboxylesterase 2 (CES2) are two predominant isoenzymes involved in both endogenous and xenobiotic metabolism, which have been extensively studied over the past decade (Satoh et al., 2002; Redinbo and Potter, 2005; Imai, 2006; Hosokawa, 2008; Wang et al., 2018; Zou et al., 2018). Both CES1 and CES2 play crucial roles in the hydrolytic metabolism of various ester xenobiotics including many ester drugs (such as oseltamivir, clopidogrel, irinotecan, and capecitabine) and environmental toxicants (such as pyrethroids) (Potter et al., 1998; Nishi et al., 2006; Zhu and Markowitz, 2009; Imai and Ohura, 2010; Zhu et al., 2013). Meanwhile, these two enzymes (CES1 and CES2) are also responsible for the hydrolysis of endogenous esters, including cholesteryl esters, triacylglycerols, and other endogenous lipids, and thus play vital physiological functions in lipid homeostasis (Alam et al., 2002; Crow et al., 2010; Wang et al., 2013; Ruby et al., 2017; Lian et al., 2018).
Cannabidiol drug interaction considerations for prescribers and pharmacists
Published in Expert Review of Clinical Pharmacology, 2022
Myfanwy Graham, Jennifer H Martin, Catherine J Lucas, Bridin Murnion, Jennifer Schneider
The esterase, carboxylesterase 1 (CES1), is expressed in the human liver and catalyzes the hydrolysis of a range of drugs and endogenous compounds. An in vitro study using the S9 fraction of human embryonic kidney 293 cells expressing CES1 observed potent inhibition of CES1 by cannabidiol. The mechanism of inhibition was reversible and observed to be a mixed competitive, noncompetitive inhibition with a mean Ki value of 0.974 μM [36]. In an in vitro study investigating the effect of cannabidiol on the two-step hydrolysis of heroin, cannabidiol was observed to be a potent in vitro inhibitor of hydrolysis. The IC50 values for the two steps of heroin hydrolysis were 14.7 and 12.1 μM, respectively. However, when the ratio of an estimated unbound cannabidiol Cmax to IC50 was calculated, the value was below the possible in-vivo drug–drug interaction FDA and European Medicines Agency cutoff value of 0.02. Based on this, the authors suggested that the observed in vitro inhibition was unlikely to be clinically relevant [37]. In a physiologically-based pharmacokinetic model, simultaneous administration of single-dose methylphenidate and cannabidiol (2.5–10 mg/kg) did not result in a significant interaction. In contrast, a mild interaction was reported to be likely with multiple cannabidiol doses (10 mg/kg twice daily) [38].
CYP2C19 and CYP3A4 activity and ADP-induced platelet reactivity in prasugrel- or ticagrelor-treated STEMI patients: monocentric study in PRAGUE-18 trial participants
Published in Xenobiotica, 2020
J. Máchal, O. Hlinomaz, K. Kostolanská, O. Peš, A. Máchalová, Z. Šplíchal, Z. Mot'ovská, J. Juřica
The metabolism of the three drugs is extensively described in our recent review (Machal & Hlinomaz, 2019). Briefly, clopidogrel is ingested as an inactive prodrug and minor part of the parent drug (approx. 15%) is activated in a two-step process by cytochrome P450 (CYP) enzymes to active thiol metabolite (Kazui et al., 2010; Savi et al., 2000). Further, its intestinal uptake is counteracted by the reverse transport by P-glycoprotein (Taubert et al., 2006), and about 80–90% of the prodrug is metabolized by carboxylesterase-1 to form inactive carboxylic acid derivative (Tang et al., 2006). Prasugrel is also a prodrug activated by a two-step process via first the intestinal carboxylesterase-2 and further by CYP (primarily by 3A4 and 2B6, and to a lesser extent by 2C9 and 2C19) (Rehmel et al., 2006). Ticagrelor is administered as an active drug, but it may be further metabolized by CYP3A4 to either active (AR-C124910XX) or inactive (AR-C133913XX) metabolite (Teng et al., 2010; Zhou et al., 2011a). Like clopidogrel, it is also a substrate of P-glycoprotein (Teng & Butler, 2013). Compared to clopidogrel, both prasugrel and ticagrelor showed better clinical efficacy (Wallentin et al., 2009; Wiviott et al., 2007), while they were found to be similarly effective in the post-MI treatment in a head-to-head comparison (Motovska et al., 2016). Whether there are patients, who could benefit from the administration of one drug more than the other, remains an open question.
Is genetic variability in carboxylesterase-1 and carboxylesterase-2 drug metabolism an important component of personalized medicine?
Published in Xenobiotica, 2020
S. Casey Laizure, Robert B Parker
Carboxylesterases are ubiquitous enzymes located in many body tissues, but the most common carboxylesterase enzymes involved in the metabolism of drugs are carboxylesterase-1 (CES1) and carboxylesterase-2 (CES2), which are found in the highest concentrations in the liver and small intestine, respectively. The blood is devoid of significant CES1 or CES2 activity making carboxylesterase prodrugs subject to first-pass metabolism in the small intestine (CES2 hydrolysis) and liver (CES1 hydrolysis) prior to reaching the systemic circulation. Thus, systemic exposure to the active metabolite of a prodrug is expected to be affected by variability in CES1 and CES2 drug metabolism, potentially making genetic variations in enzyme activity an important predictor of drug disposition and response.