Comparison of the pharmacokinetics and tolerability of montelukast/levocetirizine administered as a fixed-dose combination and as separate tablets.

OBJECTIVE: A novel fixed-dose combination (FDC) capsule of 10/5 mg of montelukast/levocetirizine may lead to better compliance than two separate tablets taken together. The aim of this study was to evaluate the pharmacokinetics (PK) and tolerability of an FDC of montelukast and levocetirizine compared to separate tablets. MATERIALS AND METHODS: A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted with healthy male subjects. In each period, either an FDC or separate tablets were administered orally, and serial blood samples were collected for PK analysis for up to 34 hours after dosing. PK parameters were calculated using noncompartmental methods. The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUClast) for the two interventions were estimated. Tolerability assessments were performed for all the subjects who received the drug at least once. RESULTS: The PK profiles of the two interventions were comparable. For montelukast, the GMRs and 90% CIs for the Cmax and AUClast were 0.9800 (0.8903 - 1.0787) and 1.0706 (0.9968 - 1.1498), respectively. The corresponding values for levocetirizine were 0.9195 (0.8660 - 0.9763) and 1.0375 (1.0123 - 1.0634), respectively. Both interventions were well tolerated. CONCLUSION: The PK and tolerability profiles of montelukast and levocetirizine after a single oral administration were comparable between the FDC and separate tablets. For patients with allergic rhinitis who require a combination treatment, the FDC of montelukast and levocetirizine will be a convenient therapeutic option.
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Pharmacokinetic behavior of montelukast in indigenous healthy male volunteers.

Aim of present study was to investigate the pharmacokinetic behavior of Montelukast in the healthy male volunteers under indigenous conditions. One tablet of montelukast 10 mg was administered in each subject and blood at different time intervals. Concentration of montelukast in plasma samples was analyzed by high performance liquid chromatography method to calculate pharmacokinetic parameters. The plasma concentration of montelukast was in the range of 1.31-1.76µg/mL at 0.5-12 hours with Cmax value of 1.59±0.16µg/mL at 3.71±0.64 hours. These values of plasma drug concentrations were above the minimum effective concentration of montelukast during the entire study hours. Absorption and elimination half-lives of the montelukast were evaluated as 2.52±0.54 hours and 2.63±0.35 hours, respectively. The volume of distribution and total body clearance of montelukast were investigated as 0.34±0.01 L/kg and 0.01±0.00 L/hr/kg, respectively. The pharmacokinetic parameters i.e. Cmax, AUC, t1/2, Vd and ClB of montelukast calculated in present study were found different as compared to that of the previous literature values which was due to genetic and environmental variation.

Biodegradable injectable in situ implants and microparticles for sustained release of montelukast: in vitro release, pharmacokinetics, and stability.

The objective of this study was to investigate the sustained release of a hydrophilic drug, montelukast (MK), from two biodegradable polymeric drug delivery systems, in situ implant (ISI) and in situ microparticles (ISM). N-Methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), triacetin, and ethyl acetate were selected as solvents. The release of 10% (w/v) MK from both systems containing poly-lactic-co-glycolic acid (PLGA) as the biodegradable polymer was compared. Upon contact with the aqueous medium, the PLGA in ISI and ISM systems solidified resulting in implants and microparticles, respectively. The in vitro drug release from the ISI system showed marked difference from miscible solvents (NMP and DMSO) than the partially miscible ones (triacetin and ethyl acetate), and the drug release decreased with increased PLGA concentration. In the ISM system, the initial in vitro drug release decreased with decreased ratio of polymer phase to external oil phase. In vivo studies in rats showed that ISM had slower drug release than the drug release from ISI. Also, the ISM system when compared to ISI system had significantly reduced initial burst effect. In vitro as well as the in vivo studies for both ISI and ISM systems showed sustained release of MK. The ISM system is suitable for sustained release of MK over 4-week period with a lower initial burst compared to the ISI system. Stability studies of the ISI and ISM formulations showed that MK is stable in the formulations stored at 4°C for more than 2 years.

Bioequivalence study of montelukast tablets in healthy Pakistani volunteers.

Montelukast is a leukotrien receptor antagonist used for asthma treatment. Objective of this study was to evaluate the bioequivalence of two montelukast 10mg tablets, Innovator drug (Singulair) as reference and other locally manufactured drug (Montiget) in 12 healthy volunteers. It was randomized, single dose, two-period crossover study with 1 week washout period. Blood samples (4-5 ml) were collected before and after drug administration and plasma was separated for analysis. Concentrations of montelukast at different time intervals were determined by validated UV-HPLC method at 345nm wavelength. Bioequivalence was assessed by using non compartmental approach and also calculated the 90% confidence interval of the least-squared pharmacokinetic parameters (Cmax, AUC0-t and AUC0-OO). On average, Cmax, AUC0-t, AUC0-inf, was 2.35µg/mL, 1.28µg.h./ml, 1.67µg.h./ml, for innovator drug and 2.53µg/mL, 1.53µg.h./ml, 1.96µg.h./ml, for test drug, respectively. Confidence interval (90%) for Cmax, AUC0-t and AUC0-inf was 89-97%, 85-91% and 81-98% respectively. No statistical difference was found between the Cmax and AUC values of test and reference drugs. The confidence intervals for Cmax, AUC0-t and AUC0-OO are fully laid within the acceptable range of FDA (80-125%), thus two formulations are considered to be bioequivalent.

Effect of clarithromycin and fluconazole on the pharmacokinetics of montelukast in human volunteers.

OBJECTIVE: Montelukast, a leukotriene receptor antagonist, is used in the treatment of asthma. The objective of the study reported here was to determine whether multiple doses of clarithromycin or fluconazole affect the pharmacokinetics of montelukast. METHODS: This was a four-phase cross-over study with a washout period of 2 weeks between phases. In phase 1, 12 volunteers received a single oral dose of 10 mg montelukast. In phase 2, the volunteers received a single, oral dose of 1,000 mg clarithromycin once daily for 2 days, followed by, on day 3, a single oral dose of 10 mg montelukast co-administered with clarithromycin. In phase 3, a single oral dose of 50 mg fluconazole was given once daily for 6 days, followed by, on day 7, a single oral dose of 10 mg montelukast co-administered with 50 mg fluconazole. In the last phase (phase 4), a single oral dose of 150 mg fluconazole was given once daily for 6 days, followed by, on day 7, a single oral dose of 10 mg montelukast co-administered with 150 mg fluconazole. The plasma concentration of montelukast was measured by high performance liquid chromatography for 24 h. RESULTS: Following clarithromycin co-administration, the area under the concentration-time curve from zero to infinity ( AUC(0-∞)) of montelukast increased by 144% [90% confidence interval (CI) 2.03-2.86]. The co-administration of a single oral dose of 150 and 50 mg fluconazole decreased the montelukast AUC(0-∞) by 30.7 (90% CI 0.53-0.81) and 38.8% (90% CI 0.57-0.69), respectively. CONCLUSIONS: Clarithromycin increased the plasma concentrations of montelukast whereas fluconazole reduced the plasma concentrations of montelukast. The mechanism of the interaction is probably due to interference of the interacting drugs with transporters mediating the uptake of montelukast.

Fluconazole but not the CYP3A4 inhibitor, itraconazole, increases zafirlukast plasma concentrations.

PURPOSE: Zafirlukast is a substrate of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 3A4 (CYP3A4) in vitro, but the role of these enzymes in its metabolism in vivo is unknown. To investigate the contribution of CYP2C9 and CYP3A4 to zafirlukast metabolism, we studied the effects of fluconazole and itraconazole on its pharmacokinetics (PK). METHODS: In a randomized crossover study, 12 healthy volunteers ingested fluconazole 200 mg (first dose 400 mg) once daily, itraconazole 100 mg (first dose 200 mg) twice daily, or placebo twice daily for 5 days, and on day 3, 20 mg zafirlukast. Plasma concentrations of zafirlukast and the antimycotics were measured up to 72 h. RESULTS: Fluconazole increased the total area under the plasma concentration-time curve (AUC) of zafirlukast 1.6-fold [95% confidence interval (CI) 1.3-2.0-fold, P < 0.001), and its peak plasma concentration 1.5-fold (95% CI 1.2-2.0-fold, P < 0.05). Fluconazole did not affect the time of peak plasma concentration or elimination half-life of zafirlukast. None of the zafirlukast PK variables differed significantly from the control in the itraconazole phase; e.g., the ratio to control of the total AUC of zafirlukast was 1.0 (95% CI 0.82-1.2) during the itraconazole phase. CONCLUSIONS: Fluconazole, but not itraconazole, increases zafirlukast plasma concentrations, strongly suggesting that CYP2C9 but not CYP3A4 participates in zafirlukast metabolism in humans.

Quantification of montelukast, a selective cysteinyl leukotriene receptor (CysLT1) antagonist in human plasma by liquid chromatography-mass spectrometry: validation and its application to a human pharmacokinetic study.

A highly sensitive, rapid assay method has been developed and validated for the estimation of montelukast (MTK) in human plasma with liquid chromatography coupled to tandem mass spectrometry with electro spray ionization in the positive-ion mode. Liquid-liquid extraction was used to extract MTK and amlodipine (internal standard, IS) from human plasma. Chromatographic separation was achieved with 10 mM ammonium acetate (pH 6.4): acetonitrile (15:85, v/v) at a flow rate of 0.50 mL/min on a Discovery HS C(18) column with a total run time of 3.5 min. The MS/MS ion transitions monitored were 586.10 --> 422.10 for MTK and 409.20 --> 238.30 for IS. Method validation and clinical sample analysis were performed as per FDA guidelines and the results met the acceptance criteria. The lower limit of quantitation achieved was 0.25 ng/mL and linearity was observed from 0.25 to 800 ng/mL. The intra-day and inter-day precisions were 5.97-8.33 and 7.09-10.13%, respectively. This novel method has been applied to a pharmacokinetic study of MTK in humans.

Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children.

BACKGROUND: Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients. METHODS: After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient's clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped. RESULTS: Fifty patients (age range: 0.7-10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient's weight was also found to be significantly corrected with montelukast clearance (p <0.0001). CONCLUSION: The developmental pharmacology of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype were found to have independent significant impacts on the clearance of montelukast.

Antileukotrienes improve naso-ocular symptoms and biomarkers in patients with NARES and asthma.

OBJECTIVE: The aim of our study was to analyze the montelukast effectiveness in improving oculonasal symptoms, patient-reported outcomes (PROs), and eosinophilic biomarkers in patients with nonallergic rhinitis eosinophilic syndrome (NARES). METHODS: We enrolled prospectively 80 symptomatic patients treated with 10 mg once a day of montelukast in monotherapy for 2 months. All patients were investigated before and after treatment. Nasal symptoms (nasal obstruction, rhinorrhoea, sneezing, nasal itching), ocular symptoms (redness/puffiness, watery eyes), and other PROs (olfactory dysfunction, difficulty going to sleep, nighttime awakenings, and nasal congestion on awakening) were scored by visual analogic scale. The following clinical scores were assessed: Total Nasal Symptom Score (T4NSS), Total Ocular Symptom Score (T2OSS), Total Symptom Score of Patient-Reported Outcomes (TSS-PROs), and a Composite Symptoms Score (CSS). Patients were classified as responders when a reduction of at least 50% of the CSS was observed. Before and after treatment, the eosinophilic biomarkers in nasal lavage were analyzed: nasal eosinophilia (number of eosinophils per high power field), eotaxin-1 and eotaxin-2. RESULTS: After treatment, significant reductions were observed for all the symptom scores. Forty-two of 78 patients were considered responders. A significant reduction of eosinophils in nasal mucosa and of levels of eotaxin-1 and eotaxin-2 in nasal lavage were observed after treatment in responder patients. Patients with asthma had an increased probability to be responders. CONCLUSION: NARES patients may benefit from treatment with montelukast. In particular, the presence of concomitant asthma may be predictive of a greater efficacy. LEVEL OF EVIDENCE: 2 Laryngoscope, 129:551-557, 2019.

A simple bioanalytical assay for determination of montelukast in human plasma: application to a pharmacokinetic study.

An analytical method based on high-performance liquid chromatographic (HPLC) was developed for the determination of montelukast in human plasma using mefenamic acid as an internal standard. After precipitation of plasma proteins with acetonitrile, chromatographic separation was carried out using a Zorbax Eclipse XDB C8 (150 mm x 4.6 mm i.d., 5 microm) with mobile phase consisted of methanol-acetonitrile-0.04M disodium hydrogen orthophosphate (22:22:56, v/v, pH 4.9). The wavelengths of fluorescence detection were set at 350 nm for excitation and 450 nm for emission. The linearity was confirmed in the concentration range of 5-1000 ng/ml in human plasma. Intra- and inter-day accuracy determined from quality control samples were 101.50 and 107.24%, and 97.15 and 100.37%, respectively. Intra- and inter-day precision measured as coefficient of variation were < or =4.72 and < or =9.00%, respectively. Extraction recoveries of drug from plasma were >48.14%. The protocol herein described was employed in a pharmacokinetic study of tablet formulation of montelukast in healthy Thai male volunteers.

Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans.

The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y12 inhibitors on montelukast pharmacokinetics. Clopidogrel (300 mg on day 1 and 75 mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P < 0.001) and decreased the M6:montelukast AUC0-7h ratio to 45% of control (90% CI 40-50%, P < 0.001). Prasugrel (60 mg on day 1 and 10 mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.

Complexation study of cinalukast and montelukast with cyclodextrines.

A fluorimetric study on the spectral characteristics of two antileukotrienes, cinalukast and montelukast, has been performed. Ionization constants of both of them have been photometrically calculated. Cinalukast pK(a) in ethanol:water 50:50 (v/v) medium resulted to be 2.2+/-0.1. Because the spectral characteristics of montelukast are widely affected by the solvent nature, pK(a) was estimated in two different ethanol:water media, 70:30 (v/v) and 10:90 (v/v) and the values calculated were pK(a)=2.9+/-0.1, and pK(a1)=2.0+/-0.1 and pK(a2)=6.5+/-0.1, respectively. It has been proven that the fluorescence of both, cinalukast and montelukast, is significantly intensified in the presence of cyclodextrins (CyDs). The host-guest complexation processes between cinalukast and alpha-CyD or heptakis-(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB) and between montelukast and DIMEB have been investigated by fluorescence spectroscopy. A 1:1 stoichiometric ratio was established for the three studied inclusion complexes. The changes produced on the fluorescence of cinalukast or montelukast, when they are included on the hydrophobic CyD cavity are used to calculate their association constants by a non-linear regression method. Semiempirical MO calculations using AM1 method were performed in order to characterize the studied inclusion complexes. A new method for cinalukast determination in human serum, based on the fluorescence of the complex cinalukast-DIMEB exhibiting limit of detection of 7.95 ng mL(-1) has been proposed with satisfactory results. Adequate recovery values between 95 and 103% were calculated at five different concentration levels.

Improving dissolution and oral bioavailability of pranlukast hemihydrate by particle surface modification with surfactants and homogenization.

The present study was carried out to develop an oral formulation of pranlukast hemihydrate with improved dissolution and oral bioavailability using a surface-modified microparticle. Based on solubility measurements, surface-modified pranlukast hemihydrate microparticles were manufactured using the spray-drying method with hydroxypropylmethyl cellulose, sucrose laurate, and water and without the use of an organic solvent. The hydrophilicity of the surface-modified pranlukast hemihydrate microparticle increased, leading to enhanced dissolution and oral bioavailability of pranlukast hemihydrate without a change in crystallinity. The surface-modified microparticles with an hydroxypropylmethyl cellulose/sucrose laurate ratio of 1:2 showed rapid dissolution of up to 85% within 30 minutes in dissolution medium (pH 6.8) and oral bioavailability higher than that of the commercial product, with approximately 2.5-fold and 3.9-fold increases in area under the curve (AUC 0 → 12 h) and peak plasma concentration, respectively. Therefore, the surface-modified microparticle is an effective oral drug delivery system for the poorly water-soluble therapeutic pranlukast hemihydrate.

Investigation of the bioequivalence of montelukast chewable tablets after a single oral administration using a validated LC-MS/MS method.

BACKGROUND: Montelukast (MT) is a leukotriene D4 antagonist. It is an effective and safe medicine for the prophylaxis and treatment of chronic asthma. It is also used to prevent acute exercise-induced bronchoconstriction and as a symptomatic relief of seasonal allergic rhinitis and perennial allergic rhinitis. OBJECTIVE: The aim of this study was to evaluate the bioequivalence (BE) of two drug products: generic MT 5 mg chewable tablets versus the branded drug Singulair(®) pediatric 5 mg chewable tablets among Mediterranean volunteers. METHODS: An open-label, randomized two-period crossover BE design was conducted in 32 healthy male volunteers with a 9-day washout period between doses and under fasting conditions. The drug concentrations in plasma were quantified by using a newly developed and fully validated liquid chromatography tandem mass spectrometry method, and the pharmacokinetic parameters were calculated using a non-compartmental model. The ratio for generic/branded tablets using geometric least squares means was calculated for both the MT products. RESULTS: The relationship between concentration and peak area ratio was found to be linear within the range 6.098-365.855 ng/mL. The correlation coefficient (R (2)) was always greater than 0.99 during the course of the validation. Statistical comparison of the main pharmacokinetic parameters showed no significant difference between the generic and branded products. The point estimates (ratios of geometric means) were 101.2%, 101.6%, and 98.11% for area under the curve (AUC)0→last, AUC0→inf, and C max, respectively. The 90% confidence intervals were within the predefined limits of 80.00%-125.00% as specified by the US Food and Drug Administration and European Medicines Agency for BE studies. CONCLUSION: Broncast(®) pediatric chewable tablets (5 mg/tablet) are bioequivalent to Singulair(®) pediatric chewable tablets (5 mg/tablet), with a similar safety profile. This suggests that these two formulations can be considered interchangeable in clinical practice.

Lack of correlation between in vitro inhibition of CYP3A-mediated metabolism by a PPAR-gamma agonist and its effect on the clinical pharmacokinetics of midazolam, an in vivo probe of CYP3A activity.

RG 12525 (2-[[4-[[2-(1H-tetrazole-5-ylmethyl)phenyl]methoxy]phenoxy]methyl] quinolone) is a novel peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist. In vitro microsomal inhibition assays indicated that RG 12525 is a potent inhibitor of CYP3A4, with a Ki value of 0.5 microM. With the conservative assumption that the total plasma concentration of drug was available to metabolic enzymes following RG 12525 oral administration, marked inhibition of CYP3A4 was expected to substantially reduce the systemic clearance of compounds metabolized by this enzyme. The possibility also existed for inhibition of intestinal and hepatic CYP3A4 by RG 12525 to reduce "first-pass" metabolism and increase absolute bioavailability of CYP3A4 substrates orally coadministered. Consequently, an in vivo drug-drug interaction study was performed to evaluate the effects of orally administered RG 12525 on in vivo CYP3A4 activity in healthy male subjects. The pharmacokinetics of oral midazolam, a probe for intestinal and hepatic CYP3A activity, was not influenced by either the low (100 mg qd for 4 days) or high (600 mg qd for4 days) RG 12525 dosing regimen despite the resulting total plasma concentrations of inhibitor that were well above in vitro Ki values. The point estimates and 90% confidence intervals for the ratios of mean midazolam AUC for subjects administered 100 mg RG 12525 (110.6; 98.7-124.1) and 600 mg RG 12525 (98.4; 84.4-114.7) versus midazolam alone were within 80% to 125%. To explain these results, factors that could limit the accuracy of in vitro models in predicting metabolic drug interactions, mainly the high degree of RG 12525 protein binding (> 99.9%), were considered. The lack of correlation between the in vitro inhibition of CYP3A4 by RG 12525 and the inconsequential effects of this compound on midazolam pharmacokinetics accentuate the need to recognize factors other than plasma drug concentrations and potency of in vitro enzyme inhibition when extrapolating in vitro data to predict in vivo drug-drug interactions.

WY-50295 tromethamine: a 5-lipoxygenase inhibitor without activity in human whole blood.

The 5-LO inhibitor, WY-50295 tromethamine (T) prevented leukotriene release (LTB4 production) in calcium ionophore stimulated, purified human and rat neutrophils. However, whereas WY-50295T inhibited both in vitro and ex vivo rat whole blood leukocyte LTB4 formation (IC50= 40 microM and oral ED50 of 18 mg/kg, respectively), it did not inhibit LTB4 production in calcium ionophore stimulated human whole blood at concentrations to 200 microM. To reduce binding of WY-50295T to serum albumin, 250 microM of a naphthalene sulfonic acid (> 99.9% binding to albumin primarily at the carboxylic site) and 250 microM sulfanilamide (binding to nonspecific sites) separately or in combination were preincubated in whole blood prior to addition of WY-50295T; however, WY-50295T still did not inhibit 5-LO and free drug blood levels were unchanged. When purified human neutrophils in the presence of fatty acid saturated albumin (fraction V) was employed, the 5-LO inhibitory activity of WY-50295T was prevented. Zileuton (5 microM) inhibited LTB4 production by 99% in the presence of these albumins. Also, rat albumin presented WY-50295T to purified rat neutrophils more effectively than human albumin (i.e. WY-50295T was more active in the presence of rat albumin). These results suggest that the high affinity binding of WY-50295T to human albumin and possibly the reduction of drug uptake (passive diffusion) using purified human vs rat neutrophils may account for the inactivity of WY-50295T in the human whole blood assay.

Comparison of effects of dexamethasone and the leukotriene D4 receptor antagonist L-708,738 on lung function and airway cytologic findings in horses with recurrent airway obstruction.

OBJECTIVE: To evaluate whether the leukotriene (LT) D4 receptor antagonist L-708,738 is therapeutically beneficial in treating horses with recurrent airway obstruction (heaves). ANIMALS: 12 adult horses with heaves and healthy lung lobes from 20 slaughtered horses. PROCEDURE: Lung lobes were used for smooth muscle tension and radioligand binding studies. Horses with heaves were given a placebo for 14 days and administered L-708,738 (n = 6; 2.5 mg/kg PO, q 12 h) or dexamethasone (6; 0.04 mg/kg, IV, q 24 h) from days 14 to 28. Pulmonary function was measured weekly for 36 days, and bronchoalveolar cells were collected on days 0,14, and 29 for cytologic examination. RESULTS: Nanomolar concentrations of L-708,738 were effective at antagonizing LTD4-induced bronchoconstriction and LTD4-receptor binding in lung lobes. Mean peak and trough L708,738 plasma concentrations during the treatment period were 1.54 and 0.28 microM, respectively. On days 21 and 29, lung mechanics were significantly improved in the dexamethasone-treated horses but not in the L-708,738-treated horses. Neither dexamethasone nor L-708,738 had a significant effect on cytologic findings. CONCLUSIONS AND CLINICAL RELEVANCE: L-708,738 was bioavailable after oral administration and sustained concentrations in plasma during the dosing period that exceeded in vitro efficacy values. However, airway function did not improve, suggesting that either drug concentrations in the lungs were subtherapeutic or that cysteinyl LT may not be important mediators of airway inflammation in heaves. Results provide the first evidence of cysteinyl LT1 receptors in airways of horses.

Simple and rapid determination of zafirlukast in plasma by ultra-performance liquid chromatography tandem mass spectrometric method: application into pharmacokinetic study in rabbits.

Zafirlukast is a selective leukotriene receptor antagonist used for the prophylaxis and chronic treatment of asthma. The aim of the present study was to develop a simple sensitive ultra-performance liquid chromatography tandem mass spectroscopy method for rapid determination of zafirlukast in plasma. After a simple one step protein precipitation by acetonitrile, zafirlukast and montelukast (IS) were separated on Acquity UPLC BEH(TM) C18 column (50 × 2.1 mm, i.d. 1.7 µm, Waters, USA) using a mobile phase of acetonitrile:water containing 10 mM acetic acid (80:20, v/v) at a flow rate of 0.3 mL/min. Zafirlukast and IS were eluted at 0.51 and 1.1 min, respectively with a total run time of only 1.5 min. The mass spectrometric determination was carried out using an electrospray interface operated in the negative mode with multiple reactions monitoring mode. The precursor to product ion transitions of m/z 574.11>462.07 and m/z 584.2>472.1 were used to quantify zafirlukast and IS, respectively. The method was linear in the concentration range of 0.17-600 ng/mL with coefficients of determination greater than 0.996 and lower limit of quantitation of 0.17 ng/mL. Intra-day and inter-day accuracies were 88.3-113.9% and the precisions were ≤ 12.6%. Zafirlukast was found to stable under various storage and sample processing conditions as per guidelines of bio-analytical method validation. The method developed herein is simple and rapid, and was successfully applied for the pharmacokinetic study in rabbits.

Effects of polymorphisms of the SLCO2B1 transporter gene on the pharmacokinetics of montelukast in humans.

Montelukast, a leukotriene receptor antagonist, is a substrate of organic anion transporting OATP2B1 encoded by the SLCO2B1. We evaluated the effects of six non-synonymous (c.1175C>T, c.1457C>T, c.43C>T, c.935G>A, c.601G>A, and c.644A>T) polymorphisms and one promoter (g.-282G>A) polymorphism on the pharmacokinetics of montelukast. A single dose of 10 mg montelukast was administered in 24 healthy subjects. Its levels were measured up to 24 hours and a pharmacokinetic analysis was performed based on the SLCO2B1 polymorphisms. We did not encounter subjects with c.1175C>T, c.43C>T, or c.644A>T polymorphisms. The remaining SLCO2B1 polymorphisms did not affect plasma levels of montelukast, and pharmacokinetic parameters of montelukast did not differ among genotype groups. Oral clearance results were as follows: (1) 3.3 L/h for c.935GG, 3.0 L/h for c.935GA, and 3.5 L/h for c.935AA; (2) 3.4 L/h for c.1457CC, 2.9 L/h for c.1457CT, and 3.2 L/h for c.1457TT; (3) 3.2 L/h for c.601GG, 3.4 L/h for c.601GA, and 3.4 L/h for c.601AA; (4) 3.2 L/h for g.-282GG, 3.4 L/h for g.-282GA, and 3.2 L/h for g.-282AA. The findings suggest that SLCO2B1 polymorphisms do not affect the pharmacokinetics of montelukast and that SLCO2B1 polymorphisms appear to be a minor determinant of inter-individual variability of montelukast.

Does desloratadine alter the serum levels of montelukast when administered in a fixed-dose combination?

OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate the serum levels of montelukast when administered alone or in combination with desloratadine. STUDY DESIGN: A prospective crossover study. METHODS: Twenty-three healthy volunteers were investigated in two sessions. Volunteers were given 10 mg of montelukast orally with 250 mL water in the first session. The same subjects were given 10 mg of montelukast in fixed combination with 5 mg desloratadine 10 days after first session. Blood samples were collected 2, 3, and 4 hours after drug administration, and kept at -80°C after both applications. Plasma samples were analyzed for montelukast concentration. RESULTS: Mean concentration values of both groups were not statistically different (P > .05), but the differences were statistically significant according to time (P < .05). Statistically significant difference was not found between the groups according to the area under curve on the basis of both marginal and cumulative values for all different time intervals (P > .05). CONCLUSIONS: The absorption rate of montelukast was not altered when administered with desloratadine. This study suggested that desloratadine does not influence the bioavailability of montelukast, and their combination therapy can be used safely.