Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enxyme induction

Labelle, Marc; Belley, Michel; Gareau, Yves; Gauthier, J. Y.; Guay, Daniel; Gordon, Robert J.; Grossman, Shlomo; Jones, Thomas R.; Leblanc, Yves; McAuliffe, Malia; Mcfarlane, C. S.; Masson, P.; Metters, Kathleen M.; Ouimet, N.; Patrick, Darryl; Piechuta, H.; Rochette, C.; Sawyer, Nicole; Xiang, Yufei; Pickett, Cecil B.; Ford‐Hutchinson, A. W.; Zamboni, Robert; Young, Robert N.

doi:10.1016/0960-894x(95)00023-m

Cited by 100 publications

(49 citation statements)

References 22 publications

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“…1,2 It is currently under development for the treatment of chronic asthma at a dose of 10 mg d 71 in adults. The safety, tolerability, gender eect, and pharmacokinetic pro®le of oral and intravenous montelukast sodium in healthy volunteers have already been evaluated.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

Zhao

Rogers

Holland

et al. 1997

Biopharm. Drug Dispos.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

Zhao

Rogers

Holland

et al. 1997

Biopharm. Drug Dispos.

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“…It could decrease inflammatory reactions mediated by leukotrienes, lower blood pressure [7][8][9] , and also used to treat asthma [10,11] , allergic rhinitis [12] and heart attack [13] . Currently, montelukast sodium is a widely prescribed for the treatment of asthma and symptoms of allergies, because of its prominent efficacy and less adverse reaction [14,15] .…”

Section: [[[(1r)-1-[3-[(e)-2-(7-chloroquinolin-2-yl)-ethenyl]phenyl]-mentioning

confidence: 99%

“…It is reported that S-and R-enantiomers of a chiral drug usually have different biological activities, one could be selected as a drug with a therapeutic action while the other to be avoided due to toxic or side effects [16,17] . As a LTD4 (leukotriene D4) receptor antagonist, montelukast sodium has a superior in vitro and in vivo compared with its S-enantiomer [7] . Based on International Conference of Harmonization (ICH) Q7 guiding principle, the S-enantiomer content in montelukast sodium bulk drug should be strictly controlled [18] .…”

Section: [[[(1r)-1-[3-[(e)-2-(7-chloroquinolin-2-yl)-ethenyl]phenyl]-mentioning

confidence: 99%

Simultaneous Determination of Montelukast Sodium S-Enantiomer and A5 Enantiomers in Montelukast Sodium Bulk Drug by Normal-Phase Chiral HPLC

Wang¹

2017

ijps

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Wang, et al.: Simultaneous Determination of Montelukast Enantiomers by Normal-Phase Chiral HPLCA sensitive and validated high performance liquid chromatographic method was developed for determination of montelukast sodium S-enantiomer, A5 and A5 R-enantiomer in montelukast sodium bulk drug. Chromatographic analysis was performed on a Daicel Chiralpak ® AD-H column at 30°, the flow rate was set 0.9 ml/min, eluent was n-hexane:isopropanol:ethanol:trifluoroacetic acid:diethylamine (65:15:20:0.1:0.1, v/v/v/v/v), determination wavelength was 280 nm and the injection volume was 10 μl. The high performance liquid chromatography was validated for system suitability, precision, limit of detection and limit of quantitation, linearity, accuracy and robustness. The results indicated that the system suitability test met the requirement with resolution more than 2.0 between montelukast sodium enantiomers and greater than 6.0 between A5 enantiomers. The values of relative standard deviation were not more than 4.0% for precision test, the limit of detection from 0.11 to 0.24 μg/ml, and the limit of quantitation from 0.22 to 0.61 μg/ml, respectively. The linearity correlation coefficients (r) were greater than 0.99 for three analytes. The recovery values were ranged from 89.35 to 108.78%. The proposed method was adequate for the determination of montelukast sodium S-enantiomer, A5 and A5 R-enantiomer in montelukast sodium bulk drug.

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“…1a), is a potent and specific cys-teinyl leukotriene D 4 (LTD 4 ) receptor antagonist [1,2], which is being used in the treatment of asthma [3][4][5][6][7][8]. The oral absorption of montelukast is rapid and complete with an average bioavailability of 63% to 73%.…”

Section: Montelukast Sodium (2-[1-[1(r)-[3-[2(e)-(7-chloroquinolin-2ymentioning

confidence: 99%

“…This injection protocol was repeated after 1,3,8,11,15,22,25, and 30 days of storage of this solution between 4 and 8°C.…”

Section: Stock Solution Stabilitymentioning

confidence: 99%

High-performance liquid chromatographic determination of montelukast sodium in human plasma: Application to bioequivalence study

Shakya¹,

Arafat²,

Hakooz³

et al. 2014

Acta Chromatographica

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Summary.A simple, sensitive, and precise high-performance liquid chromatographic (HPLC) method for quantitation of montelukast in human plasma has been developed and validated. Commercially available candesartan cilexetil was used as an internal standard. After protein precipitation, montelukast and candesartan cilexetil (I.S.) in human plasma were analyzed using mobile phase containing 62% v/v acetonitrile and 38% v/v buffer (containing 1 mL L −1 triethylamine as peak modifier, final pH adjusted to 2.5 with orthophosphoric acid). Chromatographic separation was achieved on a BDS Hypersil-C18 column (50 × 4.6 mm i.d., particle size 5 μm; Thermo Electron Corporation, USA) using isocratic elution at a flow rate of 1.5 mL min −1 . The signals were monitored using a fluorescence detector set at 350 nm for excitation and 400 nm for emission. The total time for a chromatographic separation was ~3 min. The validated quantitation ranges of this method were 5-300 ng mL −1 with coefficients of variation between 1.75% and 9.38%. Mean recoveries were 91.8 ± 3.8%. The within-and between-batch precisions were 0.74-2.46% and 1.64-7.87%, respectively. The within-and between-batch relative errors (bias) were 0.14-3.3% and 0.08-4.6%, respectively. Stability of montelukast in plasma was >94.7%, with no evidence of degradation during sample processing and 30 days storage in a deep freezer at -70°C. This validated method is sensitive and simple with between-batch precision of <8% and successfully applied for the bioequivalence studies. The formulations were compared using the following pharmacokinetic parameters: AUC 0−t , AUC 0−∞ , and C max . No statistically significant difference (p > 0.05) was observed between the logarithmically transformed AUC 0−t, AUC 0−∞ , and C max values.

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Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enxyme induction

Cited by 100 publications

References 22 publications

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

Simultaneous Determination of Montelukast Sodium S-Enantiomer and A5 Enantiomers in Montelukast Sodium Bulk Drug by Normal-Phase Chiral HPLC

High-performance liquid chromatographic determination of montelukast sodium in human plasma: Application to bioequivalence study

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