Identification of human plasma cholinesterase variants in 6,688 individuals using biochemical analysis

Jensen, Flemming; Skovgaard, L. T.; Viby‐Mogensen, J.

doi:10.1111/j.1399-6576.1995.tb04035.x

Cited by 64 publications

(37 citation statements)

References 24 publications

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“…This activity may show large variability between individuals and study populations (5,6,12). Our results are consistent with a possible systematic overestimation of plasma OC concentrations by as much as 10% during the initial phase of the pharmacokinetic profile.…”

supporting

confidence: 78%

“…Butyrylcholinesterase is important for drug activation (bambuterol, isosorbide diaspirinase) and also inactivation (suxamethonium, cocaine, and organophosphosphorus pesticides) (7). Activity is age and sex dependent (5). The genetic locus controlling butyrylcholinesterase expression is highly polymorphic (6,12), resulting in clinically significant variations in activity (1).…”

mentioning

confidence: 99%

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Rapid Degradation of Oseltamivir Phosphate in Clinical Samples by Plasma Esterases

Lindegårdh

Davies

Hien

et al. 2006

Antimicrob Agents Chemother

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The anti-influenza drug oseltamivir is an ester prodrug activated by hepatic carboxylesterases. Plasma esterases also convert up to 31.8% of the parent compound to the active metabolite after 4 h ex vivo, with wide interindividual variation. This source of error is removed by adding the esterase inhibitor dichlorvos to blood collection tubes.The threat of pandemic human H5N1 influenza has focused attention on the control and treatment of this potentially devastating disease (8). The only effective orally bioavailable antiviral agent currently licensed for this purpose is the neuraminidase inhibitor oseltamivir (OP) (13), which is being stockpiled for mass use. Although OP has been evaluated in community settings for the prevention and treatment of epidemic seasonal influenza (4), information on the therapeutic response in acute severe disease caused by the H5N1 influenza virus is limited (2).OP is an ethyl ester prodrug hydrolyzed in vivo, principally at first pass, by high-capacity hepatic carboxyesterases to the active metabolite OP carboxylate (OC) (3, 9). Oral bioavailability is approximately 80%, and OC exposure is reduced during hepatic impairment (11). Plasma concentrations of OP and OC are similar at OP peak concentration (C max 2 h postdosing, while maximum concentrations of OC (at 5 h) are typically fivefold higher than maximum concentrations of OP (3). OC is Ͻ3% bound to plasma proteins and is eliminated primarily by renal filtration and active secretion, with Ͻ5% of OP excreted unchanged by this route (3). No other metabolites have been identified to date.Human plasma contains four different esterases, butyrylcholinesterase, paraoxonase, albumin esterase, and acetylcholinesterase (7), although the last binds to the membrane of erythrocytes, which contain additional cholinesterases (10). Butyrylcholinesterase is important for drug activation (bambuterol, isosorbide diaspirinase) and also inactivation (suxamethonium, cocaine, and organophosphosphorus pesticides) (7). Activity is age and sex dependent (5). The genetic locus controlling butyrylcholinesterase expression is highly polymorphic (6, 12), resulting in clinically significant variations in activity (1). We therefore investigated whether the activity of these blood esterases after sample collection might bias the quantification of OC in blood and plasma samples by ex vivo degradation or conversion of OP into OC.The kinetics of ex vivo hydrolysis under various processing conditions were studied initially in blood obtained from a single healthy volunteer. OP (F. Hoffmann-La Roche Ltd.) dissolved in water was added to heparinized blood to produce a concentration of 10,000 ng/ml and incubated for 30 min at 37.5°C to allow equilibration. Aliquots were then exposed to three differing conditions in a complete two by two by two factorial design: storage as blood or after immediate processing as plasma, storage on ice or at 25°C, and presence or absence of the organophosphate esterase inhibitor dichlorvos (Sigma-Aldrich) at a concentration of 200 g/ml blo...

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supporting

confidence: 78%

mentioning

confidence: 99%

Rapid Degradation of Oseltamivir Phosphate in Clinical Samples by Plasma Esterases

Lindegårdh

Davies

Hien

et al. 2006

Antimicrob Agents Chemother

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“…Similar frequencies have been observed in populations of different ethnic and geographic origins (Souza et al, 1998) and our results (0.19) are consistent with these studies. Other BCHE deficiency variants are uncommon, such as the dibucaine-resistant atypical variant (BCHE-A), with an allele frequency from 1.5% to 7.3% in European populations (Acuña et al, 2003;Jensen et al, 1995;Lockridge, 1992). The allele frequency observed in our study (2%) falls within this range.…”

Section: Discussionsupporting

confidence: 47%

Polymorphisms of pesticide-metabolizing genes in children living in intensive farming communities

et al. 2015

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“…They were selected, as was their final concentration in the assay, based on the literature: edetic acid (EDTA) and chloromercuribenzoate (1 mM and 100 M, respectively; in-hibitors of A-esterases), paraoxon, physostigmine, metoclopramide, sodium fluoride (NaF), and bis-pnitrophenyl phosphate (BNPP) (all at 100 M; inhibitors of B-esterases), acetazolamide (100 M, inhibitor of carboxylanhydrase), and acetylsalicylic acid (100 M; aspecific inhibitor of esterases) (18)(19)(20)(21)(22)(23). Incubation mixtures contained whole blood (980 l), 700 M LEV (added as 10 l in water), and the inhibitor (added as 10 l in either water or methanol).…”

Section: In Vitro Assay For Levetiracetam Hydrolysis By Using Human Lmentioning

confidence: 99%

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

2003

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Summary:Purpose: The novel antiepileptic drug (AED) levetiracetam (LEV; Keppra) has a wide therapeutic index and pharmacokinetic characteristics predicting limited druginteraction potential. It is indicated as an add-on treatment in patients with epilepsy, and thus coadministration with valproic acid (VPA) is likely. These studies were performed to determine whether coadministration of LEV with VPA might result in pharmacokinetic interactions.Methods: In vitro assays were performed to characterize the transformation of LEV into its main in vivo metabolite UCB L057. The reaction was examined for its sensitivity to clinically relevant concentrations of VPA. An open-label, one-way, onesequence crossover clinical trial was conducted in 16 healthy volunteers to assess further the possibility of any relevant pharmacokinetic interaction. Results:Human whole blood and, to a lesser extent, human liver homogenates were demonstrated to hydrolyze LEV to UCB L057, its main metabolite. The reaction possibly involves type-B esterases and is not affected by 1 mM VPA (i.e., 166 g/ml). Pharmacokinetic parameters of a single dose of LEV (1,500 mg) coadministered with steady-state concentrations of VPA (8 days of 500 mg, b.i.d.) did not differ significantly from the pharmacokinetics of LEV administered alone [area under the curve (AUC) of 397 and 400 g/h/ml, respectively]. Furthermore, LEV did not affect the steady-state pharmacokinetics of VPA.Conclusions: These findings suggest the absence of a pharmacokinetic interaction between VPA and LEV during shortterm administration, and suggest that dose adjustment is not required when these two drugs are given together.

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Identification of human plasma cholinesterase variants in 6,688 individuals using biochemical analysis

Cited by 64 publications

References 24 publications

Rapid Degradation of Oseltamivir Phosphate in Clinical Samples by Plasma Esterases

Rapid Degradation of Oseltamivir Phosphate in Clinical Samples by Plasma Esterases

Polymorphisms of pesticide-metabolizing genes in children living in intensive farming communities

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

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