piperidines and montelukast

The antidiabetic repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and CYP3A4. Telithromycin, an antimicrobial agent, inhibits CYP3A4 in vitro and in vivo. Montelukast, an antiasthmatic drug, is a potent inhibitor of CYP2C8 in vitro. We studied the effects of telithromycin, montelukast, and the combination of telithromycin and montelukast on the pharmacokinetics and pharmacodynamics of repaglinide.. In a randomized 4-phase crossover study, 12 healthy volunteers received 800 mg telithromycin, 10 mg montelukast, both telithromycin and montelukast, or placebo once daily for 3 days. On day 3, they ingested a single 0.25-mg dose of repaglinide. Plasma and urine concentrations of repaglinide and its metabolites M1, M2, and M4, as well as blood glucose concentrations, were measured for 12 hours.. Telithromycin alone raised the mean peak plasma repaglinide concentration to 138% (range, 91%-209%; P = .006) and the total area under the plasma concentration-time curve from 0 hours to infinity [AUC0-infinity] of repaglinide to 177% (range, 125%-257%; P < .001) of control (placebo). Telithromycin reduced the AUC0-infinity ratio of the metabolite M1 to repaglinide by 68% (P < .001) and the urinary excretion ratio of M1 to repaglinide by 77% (P = .001). In contrast to previous estimates based on in vitro CYP2C8 inhibition data, montelukast had no significant effect on the pharmacokinetics of repaglinide or its metabolites and did not significantly alter the effect of telithromycin on repaglinide pharmacokinetics. Telithromycin, unlike montelukast, lowered the maximum blood glucose concentration (P = .002) and mean blood glucose concentration from 0 to 3 hours (P = .008) after repaglinide intake, as compared with placebo.. Telithromycin increases the plasma concentrations and blood glucose-lowering effect of repaglinide by inhibiting its CYP3A4-catalyzed biotransformation and may increase the risk of hypoglycemia. Unexpectedly, montelukast has no significant effect on repaglinide pharmacokinetics, suggesting that it does not significantly inhibit CYP2C8 in vivo. The low free fraction of montelukast in plasma may explain the lack of effect on CYP2C8 in vivo, despite the low in vitro inhibition constant, highlighting the importance of incorporating plasma protein binding to interaction predictions.

Topics: Acetates; Adolescent; Adult; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Biotransformation; Blood Glucose; Carbamates; Cross-Over Studies; Cyclopropanes; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Humans; Hypoglycemic Agents; Ketolides; Leukotriene Antagonists; Male; Piperidines; Quinolines; Sulfides

The fixed-dose combination (FDC) of montelukast sodium (MLS) and bilastine (BIL) is used for monotherapy in the patient with seasonal allergic rhinoconjuctivitis and asthma. According to the upcoming ICH (International Council for Harmonization) Q14 guideline, the development of the analytical method by the implementation of the Analytical Quality by Design (AQbD) approach based on principles of Quality Risk Management (QRM) and design of experiments (DoE) would be a regulatory requirement for the registration of new drug substance and product in ICH countries. Hence, a robust high-performance thin layer chromatography method has been developed, which was not previously reported for simultaneous estimation of MLS and BIL using risk and DoE-based enhanced AQbD approach. The analytical failure mode effect analysis (AFMEA) was started with the identification of potential analytical failure modes followed by their effect analysis by RPN ranking and filtering method. The DoE-based AFMEA was applied for optimization of high-risk analytical failure modes by central composite design using Design-Expert software. The method operable design ranges and control strategy was set for quality risk management throughout the lifecycle of the developed method. The developed method was validated as per ICH Q2 (R1) guideline. The method was applied for the assay of FDC, and results were found in compliance with the labeled claim.

Topics: Acetates; Benzimidazoles; Chromatography, Thin Layer; Cyclopropanes; Humans; Piperidines; Quinolines; Research Design; Sulfides

Concomitant montelukast and bilastine are used as additive therapy for seasonal allergic rhinoconjuctivitis and mild to moderate asthma. According to a literature review, no UV-visible spectrophotometric method has been reported yet for simultaneous estimation of montelukast sodium and bilastine in their combined pharmaceutical dosage forms.. Five different multicomponent spectrophotometric methods were therefore developed and validated for simultaneous estimation of montelukast sodium and bilastine using a risk assessment-based enhanced analytical quality-by-design approach.. The identification and assessment of method risk parameters were carried out using the risk priority number ranking and filtering method according to the International Conference on Harmonization (ICH) Q9 guideline. The wavelength for detection and solvents such as 0.1 N NaOH and 0.1 N HCl were found to be critical method parameters for the development of the target methods. The developed methods were validated as per the ICH Q2(R1) guideline.. The developed and validated methods were applied for assay of combined pharmaceutical dosage forms of montelukast sodium and bilastine and results were found to be in good agreement with their label claims.. The developed methods did not include the usage of any organic solvent and are a good alternative to the costly chromatography method. Hence, the methods are eco-friendly and economical for the simultaneous estimation of bilastine and montelukast sodium.. Five multicomponent spectrophotometric methods were developed for simultaneous estimation of montelukast sodium and bilastine using a risk-based analytical quality-by-design approach. An assay of combined tablet dosage forms of montelukast sodium and bilastine was then carried out using the developed methods.

Topics: Acetates; Benzimidazoles; Cyclopropanes; Piperidines; Quinolines; Risk Assessment; Sulfides

Nasal obstruction is one of the most bothersome symptoms of allergic rhinitis (AR) affecting sleep-related quality of life in AR patients. Although several treatments were tested to control nasal obstruction, some patients with moderate to severe AR do not respond to current treatments, including the combined administration of different types of anti-allergic medicine. Thus, new options for AR treatment are needed. This study aimed to evaluate the effects of combined treatment with a novel inhibitor of hematopoietic prostaglandin D synthase (HPGDS), TAS-205, and different types of anti-allergic medicine on nasal obstruction in AR. Firstly, we demonstrated that TAS-205 selectively inhibited prostaglandin D

Topics: Acetates; Animals; Anti-Allergic Agents; Cell Line; Cyclopropanes; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Guinea Pigs; Humans; Intramolecular Oxidoreductases; Lipocalins; Male; Morpholines; Nasal Mucosa; Nasal Obstruction; Ovalbumin; Piperidines; Prostaglandin D2; Pyrroles; Quality of Life; Quinolines; Rats; Rhinitis, Allergic; Sulfides; Terfenadine

Topics: Acetates; Anti-Asthmatic Agents; Asthma; Benzimidazoles; Cyclopropanes; Humans; Piperidines; Quinolines; Seasons; Sulfides

We have previously reported that the microsomal activities of CYP2C8 and CYP3A4 largely depend on the buffer condition used in in vitro metabolic studies, with different patterns observed between the 2 isozymes. In the present study, therefore, the possibility of buffer condition dependence of the fraction metabolized by CYP2C8 (fm2C8) for repaglinide, a dual substrate of CYP2C8 and CYP3A4, was estimated using human liver microsomes under various buffer conditions. Montelukast and ketoconazole showed a potent and concentration-dependent inhibition of CYP2C8-mediated paclitaxel 6α-hydroxylation and CYP3A4-mediated triazolam α-hydroxylation, respectively, without dependence on the buffer condition. Repaglinide depletion was inhibited by both inhibitors, but the degree of inhibition depended on buffer conditions. Based on these results, the contribution of CYP2C8 in repaglinide metabolism was estimated to be larger than that of CYP3A4 under each buffer condition, and the fm2C8 value of 0.760, estimated in 50 mM phosphate buffer, was the closest to the value (0.801) estimated in our previous modeling analysis based on its concentration increase in a clinical drug interaction study. Researchers should be aware of the possibility of buffer condition affecting the estimated contribution of enzyme(s) in drug metabolism processes involving multiple enzymes.

Topics: Acetates; Buffers; Carbamates; Cyclopropanes; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Humans; Hypoglycemic Agents; Ketoconazole; Microsomes, Liver; Piperidines; Quinolines; Sulfides

Allergic rhinitis (AR) is a global health problem that affects a large number of population. Piperine (PIP) has been reported to exhibit anti-inflammatory, anti-histaminic, and immunomodulatory activities; however, its antiallergic profile has not been studied.. The objective of the study was to investigate the antiallergic potential of PIP in ova-albumin (OVA)-induced AR, mast cell degranulation (MSD), and OVA-induced paw edema.. Mice were sensitized with OVA alternately on 1, 3, 5, 7, 9, 11, and 13th day. They were treated with either vehicle, PIP (10, 20, and 40 mg/kg, p.o.), or montelukast (10 mg/kg, p.o.) from the 14th to 20th day. On the 21st day, intranasal (OVA: 5% µl) challenge was done. Animals were evaluated for physiological parameters, biochemical parameters, spleen weight, expression of interleukins (IL-6 and IL-1β), and immunoglobin-E (IgE). Histopathology of nasal mucosa, lungs, and spleen was carried out. MSD and paw edema studies were made to understand the mechanism of action.. PIP (10, 20, and 40 mg/kg, p.o.) showed a significant dose-dependent protection with respect to nasal rubbing, redness of nose, and sneezing (p < 0.001) following nasal challenge. PIP dose dependently reduced histamine, NO concentration (p < 0.001), as well as reduced expression of IL-6, IL-1β, and IgE (p < 0.001) as compared with the control group. Histopathology showed inhibition of infiltration of eosinophils and hyperplasia. It dose dependently reduced MSD and paw edema (p < 0.001).. PIP acts by mast cell-stabilizing activity, exhibits immunomodulatory and anti-inflammatory activity, thereby providing an effective treatment for AR.

Topics: Acetates; Alkaloids; Animals; Anti-Allergic Agents; Benzodioxoles; Biomarkers; Cell Degranulation; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Eosinophils; Histamine; Immunoglobulin E; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Mast Cells; Nitric Oxide; Ovalbumin; Piperidines; Polyunsaturated Alkamides; Quinolines; Rhinitis, Allergic; Spleen; Sulfides; Time Factors

Understanding the potential for cytochrome P450 (P450)-mediated drug-drug interactions is a critical step in the drug discovery process. Although in vitro studies with CYP3A4, CYP2C9, and CYP2C19 have suggested the presence of multiple binding regions within the P450 active site based on probe substrate-dependent inhibition profiles, similar studies have not been performed with CYP2C8. The ability to understand CYP2C8 probe substrate sensitivity will enable appropriate in vitro and in vivo probe selection. To characterize the potential for probe substrate-dependent inhibition with CYP2C8, the inhibition potency of 22 known inhibitors of CYP2C8 were measured in vitro using four clinically relevant CYP2C8 probe substrates (montelukast, paclitaxel, repaglinide, and rosiglitazone) and amodiaquine. Repaglinide exhibited the highest sensitivity to inhibition in vitro. In vitro phenotyping indicated that montelukast is an appropriate probe for CYP2C8 inhibition studies. The in vivo sensitivities of the CYP2C8 probe substrates cerivastatin, fluvastatin, montelukast, pioglitazone, and rosiglitazone were determined in relation to repaglinide on the basis of clinical drug-drug interaction (DDI) data. Repaglinide exhibited the highest sensitivity in vivo, followed by cerivastatin, montelukast, and pioglitazone. Finally, the magnitude of in vivo CYP2C8 DDI caused by gemfibrozil-1-O-β-glucuronide was predicted. Comparisons of the predictions with clinical data coupled with the potential liabilities of other CYP2C8 probes suggest that montelukast is an appropriate CYP2C8 probe substrate to use for the in vivo situation.

Topics: Acetates; Amodiaquine; Aryl Hydrocarbon Hydroxylases; Binding Sites; Carbamates; Cyclopropanes; Cytochrome P-450 CYP2C8; Drug Interactions; Humans; Microsomes, Liver; Paclitaxel; Piperidines; Quinolines; Rosiglitazone; Sensitivity and Specificity; Substrate Specificity; Sulfides; Thiazolidinediones