Species differences in hydrolysis of isocarbacyclin methyl ester (TEI-9090) by blood esterases

Minagawa, Toshiya; Kohno, Yoshiro; Suwa, Toshio; Tsuji, Akira

doi:10.1016/0006-2952(95)00071-7

Cited by 69 publications

(49 citation statements)

References 27 publications

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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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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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“…26) Nevertheless, the esterase is responsible for the hydrolysis of TEI-9090. 23) Neither acetylcholinesterase nor carboxylesterase appears to be involved in the GB hydrolysis because the activity was insensitive to PMSF, DFP, and BW284C51.…”

Section: Discussionmentioning

confidence: 99%

“…An erythrocyte arylesterase is known as one of the DTNB-sensitive esterases. 20) This esterase has been shown to be localized in the cytosol of erythrocytes 21) and hydrolyzes a small number of drugs containing aspirin, 20) esmolol, 22) TEI-9090 (isocarbacyclin methyl ester), 23) and nafamostat. 10) However, characteristics of the enzyme have not been fully understood.…”

Section: Discussionmentioning

confidence: 99%

Butyrylcholinesterase and Erythrocyte Sulfhydryl-dependent Enzyme Hydrolyze Gabexate in Human Blood

Yamaori

Kushihara

Fujiyama

et al. 2007

JOURNAL OF HEALTH SCIENCE

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Gabexate (GB), a serine protease inhibitor that is widely used for the treatment of acute pancreatitis and disseminated intravascular coagulation, has been reported to be partly hydrolyzed by human serum albumin. However, other enzymes responsible for GB hydrolysis in human blood remain unclear. In this study, we examined in vitro metabolism of GB with human blood samples. The hydrolytic activities of the plasma and erythrocytes at 100 µM of GB were 167 ± 26 and 151 ± 9 nmol/min/ml blood fraction (mean ± S.D., n = 8), respectively. Kinetic analysis indicated that V max and K m values were 1.75 µmol/min/ml blood fraction and 529 µM for the plasma and 10.6 µmol/min/ml blood fraction and 7360 µM for the erythrocytes, respectively. The activity of human plasma was inhibited by ethopropazine, a butyrylcholinesterase inhibitor (27% inhibition at 100 µM). Furthermore, the plasma activity was inhibited by 5,5 -dithiobis(2-nitrobenzoic acid) (DTNB) (40% inhibition at 5000 µM), suggesting the involvement of albumin in the plasma GB hydrolysis. The erythrocyte activity was also decreased by DTNB (56% inhibition at 5000 µM), implying that this activity was dependent on the presence of sulfhydryl group(s), while little or no inhibition of the activity was seen with phenylmethylsulfonyl fluoride, diisopropyl fluorophosphate, and BW284C51. Butyrylcholinesterase from human serum showed GB hydrolytic activity with V max of 363 nmol/min/mg protein and K m of 263 µM. These results suggest that, in addition to albumin, butyrylcholinesterase and erythrocyte sulfhydryl-dependent enzyme are responsible for GB hydrolysis in human blood.

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“…8) Until now, no one has given a quantitative method to estimate the relative contribution of blood and tissue for these drugs hydrolysis. Based on our hypothesis that the drug that was directly hydrolyzed in blood was excreted into urine, we estimated the rate of blood hydrolysis.…”

Section: Discussionmentioning

confidence: 99%

“…In humans, a blood half-life of nafamostat elimination was approximately 23 min and longer than rats, 7) which can be explained by higher esterase activities of rat blood. 8) Accordingly, the contribution of human tissue to the nafamostat hydrolysis would be larger than that of rat, which suggests that, in addition to the blood, tissue esterase may be other important metabolic sites of nafamostat. According to the species differences, some researchers have conducted the nafamostat metabolism in vitro experiments and compared the relative activity of liver and blood esterase for nafamostat hydrolysis.…”

mentioning

confidence: 99%

An in Vivo Approach for Globally Estimating the Drug Flow between Blood and Tissue for Nafamostat Mesilate: the Main Hydrolysis Site Determination in Human

Cao

Chen

Hao

et al. 2008

Biological & Pharmaceutical Bulletin

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Nafamostat mesilate, an ester drug with extensive hydrolysis in vivo, exhibits species difference in the relative contribution for its hydrolysis in blood and tissues. For the rat, the main hydrolysis site may be blood and human may be tissue (mainly by liver). The paper gave in vivo evidence that human tissue may give more contribution for its hydrolysis. In the initial phase of drug administration, the drug accumulating level in tissue was low; the efflux fraction from tissue into blood can be ignorable comparing with the drug influx into tissue. Based on urine and plasma metabolite analysis, we concluded that in the initial phase almost all the drug hydrolysis in blood was excreted into urine. Then according to the initial urine metabolite analysis, we can estimate the drug hydrolysis rate in blood. The rate of drug diffusion from blood into tissues can be deduced based on the mass balance analysis of the initial blood drug. With the estimated rate constants, the drug efflux from tissues into blood was calculated according to equation: OF T-B (efflux from tissues)‫؍‬OF B-U (blood hydrolysis fraction)؉OF B-T (influx into tissues)؊D B (hydrolysis in blood). The net flow (influent flux minus effluent flux) represented the drug hydrolysis fraction in tissue. As the result indicated, in human about 20% drug administrated was hydrolyzed in blood and nearly 80% in tissues. The relative hydrolysis fraction indicated that the main hydrolysis site in human body may locate in tissue, which was different to rats.

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Species differences in hydrolysis of isocarbacyclin methyl ester (TEI-9090) by blood esterases

Cited by 69 publications

References 27 publications

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

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

Butyrylcholinesterase and Erythrocyte Sulfhydryl-dependent Enzyme Hydrolyze Gabexate in Human Blood

An in Vivo Approach for Globally Estimating the Drug Flow between Blood and Tissue for Nafamostat Mesilate: the Main Hydrolysis Site Determination in Human

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