Simultaneous determination of nerisopam, a novel anxiolytic agent showing polymorphic metabolism, and its N-acetyl metabolite from human plasma by a validated high-performance liquid chromatographic method

Róna, Kálmán; Ary, K; Gachályi, B; Klebovich, Imre; Tomori, É.

doi:10.1016/0378-4347(95)00289-8

Cited by 7 publications

(4 citation statements)

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“…Amino substituents, which are resistant to oxidative metabolism, are frequently acetylated ( Levsen et al 2005). A similar N-acetylation was observed for talampanel (Buchwald et al 2005) and nerisopam (Rona et al 1996). O-demethylation of two methoxy moieties (M9) and ring hydroxylation (M13) were also detected in KR31378 metabolites at trace levels.…”

Section: Discussionmentioning

confidence: 62%

Disposition and metabolism of (2S,3S,4R)-N′′-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N′-benzylguanidine, a novel neuroprotective agent for ischemia-reperfusion damage, in rats

et al. 2007

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The metabolism and disposition of KR31378 (a benzopyran derivative and a novel neuroprotective agent) were investigated following single oral or intravenous administration of [(14)C]-KR31378 to rats. [(14)C]-KR31378 was rapidly absorbed after oral dosing with an oral bioavailability of greater than 71%. The maximum plasma concentration and area under the curve of total radioactivity in rat plasma increased proportionally to the administered dose. KR31378 was distributed over all organs and tissues except for brain, eyeball and testis, and declined by first order kinetics up to 24 h after dosing. Excretion of the radioactivity was 29.5% of the dose in the urine and 58.5% in the feces within 2 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 66.0% for the first 24 h. KR31378 was extensively metabolized by ring hydroxylation, O-demethylation, oxidation and reduction with subsequent N-acetylation and O-glucuronide conjugation. N-acetylated conjugates (M2, M10, M11, M12, M14, and M15) were identified as the predominant metabolites in rats.

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Section: Discussionmentioning

confidence: 62%

Disposition and metabolism of (2S,3S,4R)-N′′-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N′-benzylguanidine, a novel neuroprotective agent for ischemia-reperfusion damage, in rats

et al. 2007

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“…4 and 5). When correlation was calculated between acetylation of NER/NAT2 SMZ and GYKI47261/NAT2 SMZ , respectively, the correlation [Chung et al, 1993] 0.05 M acetic acid:acetonitrile, 86:14, (vol/vol) 1.2 mL/min 266 PAS [Andres et al, 1986] Perchloric acid (pH 1.8): acetonitrile:methanol, 75:12.5:12.5, (vol/vol/vol) 1 mL/min 270 PROC [Andres et al, 1986] 0.15% Triethylamine, trifluoroacetate (pH 3.5) :acetonitrile, 92:8, (vol/vol) 1.2 mL/min 268 AF [Chung et al, 1993] 0.02 M KH 2 PO 4 , phosphoric acid (pH 4.5):acetonitrile 53:47, (vol/vol) 1 mL/min 280 NER [Ró na et al, 1996] 0.04 M phosphoric acid, 2 mM heptanesulfonic acid, triethylamine (pH 2. In the case of NER, a human phase I experiment has been performed with 12 volunteers, and proved in vivo polymorphic acetylation [Ró na et al, 1997] in accordance with our in vitro results.…”

Section: Resultsmentioning

confidence: 99%

Prediction of polymorphic N‐acetylation of new drug candidates by correlation with human NAT1 and NAT2

Jemnitz

Vereczkey

2002

Drug Development Research

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Due to interindividual variation in N-acetyltransferase 2 (NAT2) activity, pharmaceutical companies face the problem of polymorphic metabolism in drugs that are metabolized mainly or exclusively by this enzyme. An in vitro method has been developed to predict in vivo polymorphic Nacetylation at an early stage of drug development. Two new type 5H-2,3-benzodiazepine derivatives, Nerisopam (NER) with anxiolytic activity and GYKI47261 with antiepileptic activity, are metabolized mainly by N-acetylation in the rat and human. The selectivity of human N-acetyltransferases (NAT1,2) to form the acetylated metabolites has been investigated by correlation analysis. Twelve human liver samples were characterized for NAT1 and NAT2 phenotype based on their enzyme activity toward two selective NAT1 (p-aminobenzoic acid, PABA; p-aminosalicylic acid, PAS) and two selective NAT2 (sulfamethazine, SMZ; procainamide, PROC) substrates. Significant correlation was found between enzyme activities NAT1 PABA /NAT1 PAS and NAT2 SMZ /NAT2 PROC , respectively, and no correlation was observed comparing enzyme activities toward NAT1 PABA /NAT2 PROC . Enzyme activities using NER and GYKI 47261 as substrates were compared to activities obtained with NAT1 and NAT2 selective substrates, and the correlation coefficients were calculated. Good correlation was established between the rates of acetylation of the two drugs and that of the NAT2 selective substrate (NER/NAT2 SMZ , r 2 ¼ 0.91, GYKI 47261/ NAT2 SMZ , r 2 ¼ 0.91). In contrast, no correlation was found between the rate of conjugation of the drugs and that of NAT1 selective substrate (NER/NAT1 PABA , r 2 ¼ 0.022, GYKI 47261/NAT1 PABA , r 2 ¼ 0.0004), suggesting polymorphic in vivo metabolism, since both drugs are acetylated preferably by NAT2. According to our results, correlation analysis based on in vitro acetylation activity may be used to predict in vivo polymorphic metabolism. Drug Dev.

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“…An HPLC separation chromatogram is presented in Figure 2, where a blank plasma sample and an 500 ng ambroxol and 500 ng internal standard [6] containing spiked plasma sample are shown on the same figure. In each case pooled dog plasma was used.…”

Section: Resultsmentioning

confidence: 99%

“…Ambroxol and the internal standard nerisopam (EGIS-6775) [ [6] were from EGIS Pharmaceuticals (Budapest, Hungary). Acetonitrile and methanol were from Romil (Cambridge, England); phosphoric acid (85 %) and ammoniumcarbonate were from Fluka Chemie AG, (Buchs, Switzerland); potassiumhydrogenphosphate, tetrahydrofuran, and triethlamine were from Merck (Darmstadt, Germany).…”

Section: Experimental Materialsmentioning

confidence: 99%

Determination of ambroxol in dog plasma by high-performance liquid chromatography and UV detection

et al. 2000

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Simultaneous determination of nerisopam, a novel anxiolytic agent showing polymorphic metabolism, and its N-acetyl metabolite from human plasma by a validated high-performance liquid chromatographic method

Cited by 7 publications

References 1 publication

Disposition and metabolism of (2S,3S,4R)-N′′-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N′-benzylguanidine, a novel neuroprotective agent for ischemia-reperfusion damage, in rats

Disposition and metabolism of (2S,3S,4R)-N′′-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N′-benzylguanidine, a novel neuroprotective agent for ischemia-reperfusion damage, in rats

Prediction of polymorphic N‐acetylation of new drug candidates by correlation with human NAT1 and NAT2

Determination of ambroxol in dog plasma by high-performance liquid chromatography and UV detection

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