Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma

Li, Bin; Sedlacek, Meghan; Manoharan, Indumathi; Boopathy, Rathanam; Duysen, Ellen G.; Masson, Patrick; Lockridge, Oksana

doi:10.1016/j.bcp.2005.09.002

Cited by 480 publications

(398 citation statements)

References 70 publications

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“…This could depend on the higher esterase activity of the latter, as well as differences in enzyme composition. 65 In rat plasma, the cleavage of 24b seems to be mainly dependent on the combined action of carboxylesterase and cholinesterase. In fact, while EDTA did not change the stability of the compound (t 1/2 = 0.53 min vs 0.34 min in the presence of EDTA), BNPP, PMSF, and eserine markedly increased the half-life of 24b.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 97%

“…Briefly, rat and human plasma were preincubated in the presence of selected inhibitors or vehicle according to literature conditions. 65 After preincubation, compound 24b was added, and at regular time points, aliquots of the sample (50 μL) were withdrawn, processed, and analyzed as reported for in vitro rat plasma stability assays.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

et al. 2012

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The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure−activity and structure−property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC 50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 97%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

et al. 2012

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“…Human plasma contains only three esterases: albumin, BuChE and paraoxonase [14,15]. To rule out the possibility that the AAA activity of HSA is due to contamination by paraoxonase, the AAA activity of highly purified human PON1 was tested.…”

Section: Absence Of Contaminating Enzymes In Faf-hsamentioning

confidence: 99%

Aryl acylamidase activity of human serum albumin witho-nitrotrifluoroacetanilide as the substrate

Masson

Froment

Darvesh

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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Albumin is generally regarded as an inert protein with no enzyme activity. However, albumin has esterase activity as well as aryl acylamidase activity. A new acetanilide substrate, o-nitrotrifluoroacetanilide (o-NTFNAC), which is more reactive than the classical o-nitroacetanilide, made it possible to determine the catalytic parameters for hydrolysis by fatty-acid free human serum albumin. Owing to the low enzymatic activity of albumin, kinetic studies were performed at high albumin concentration (0.075 mM). The albumin behavior with this substrate was Michaelis-Menten like. Kinetic analysis was performed according to the formalism used for catalysis at high enzyme concentration. This approach provided values for the turnover and dissociation constant of the albumin-substrate complex: k cat ¼ 0.13^0.02 min2 1 and K s ¼ 0.67^0.04 mM. MALDI-TOF experiments showed that unlike the ester substrate p-nitrophenyl acetate, o-NTFNAC does not form a stable adduct (acetylated enzyme). Kinetic analysis and MALDI-TOF experiments demonstrated that hydrolysis of o-NTFNAC by albumin is fully rate-limited by the acylation step (k cat ¼ k 2 ). Though the aryl acylamidase activity of albumin is low (k cat /K s ¼ 195 M 21 min 21 ), because of its high concentration in human plasma (0.6 -1 mM), albumin may participate in hydrolysis of aryl acylamides through second-order kinetics. This suggests that albumin may have a role in the metabolism of endogenous and exogenous aromatic amides, including drugs and xenobiotics.

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“…It is wellknown that rat plasma has additional esterases (e.g., carboxylesterases and cholinesterases) compared to higher species. 14 Higher mammalian species including humans express many of these esterases in liver. 15 It is expected that in vitro hydrolysis of the prodrugs in the rat plasma may be more pronounced than corresponding hydrolysis in the plasma of other mammalian species.…”

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confidence: 99%

Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

Singh

Rindgen

Bradley

et al. 2013

ACS Med. Chem. Lett.

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Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.

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Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma

Cited by 480 publications

References 70 publications

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

Aryl acylamidase activity of human serum albumin witho-nitrotrifluoroacetanilide as the substrate

Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

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