ABSTRACT
Olmesartan medoxomil (OM) is hydrolyzed to its active metabolite olmesartan by the action of aryl esterase to exert its antihypertensive actions by selectively blocking angiotensin II-AT1 receptor. Poor aqueous solubility and uncontrolled enzymatic conversion of OM to its poorly permeable olmesartan limits its oral bioavailability. The aim of the current study was to formulate a novel nanoemulsion of OM to improve its pharmacokinetics and therapeutic efficacy. The oil-in-water (o/w) nanoemulsion of OM was developed using lipoid purified soybean oil 700, sefsol 218 and solutol HS 15. We have characterized the nanoemulsions by considering their thermodynamic stability, morphology, droplet size, zeta potential and viscosity and in vitro drug release characteristics in fasting state simulated gastric fluid (pH 1.2) and intestinal fluid (pH 6.5). The thermodynamically stable nanoemulsions comprises of spherical nanometer sized droplets (<50 nm) with low polydispersity index showed enhanced permeability through the Caco-2 cell monolayer. The concentration of active olmesartan in rat plasma following oral absorption study was determined by our validated LC-MS/MS method. The result of the pharmacokinetic study showed 2.8-fold increased in area under the curve (AUC0-27) of olmesartan upon oral administration of OM nanoemulsion and sustained release profile. Subsequent, in vivo studies with nanoemulsion demonstrated better and prolonged control of experimentally induced hypertension with 3-fold reduction in conventional dose. By analysing the findings of the present investigations based on stability study, Caco-2 permeability, pharmacokinetic profile and pharmacodynamic evaluation indicated that the nanoemulsion of OM (OMF6) could significantly enhance the oral bioavailability of relatively insoluble OM contributing to improved clinical application.
Subject(s)
Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Imidazoles/pharmacology , Imidazoles/therapeutic use , Tetrazoles/pharmacology , Tetrazoles/therapeutic use , Absorption , Administration, Oral , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacokinetics , Blood Pressure/drug effects , Caco-2 Cells , Cell Membrane Permeability/drug effects , Electric Conductivity , Emulsions , Humans , Hydrogen-Ion Concentration , Hypertension/physiopathology , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Male , Nanoparticles/ultrastructure , Olmesartan Medoxomil , Particle Size , Rats , Rats, Wistar , Refractometry , Static Electricity , Tetrazoles/administration & dosage , Tetrazoles/pharmacokinetics , Thermodynamics , Viscosity/drug effectsABSTRACT
CONTEXT: Andrographis paniculata (Burm.f.) Nees (Acanthaceae) is widely used in tribal medicine in India and some other countries for multiple clinical applications. It contains andrographolide (AG) (diterpenoid lactone), a major phytomarker which probably accounts for its medicinal properties. OBJECTIVE: This study investigates the site-specific distribution of AG in different tissues of rats and its pharmacokinetic parameter evaluation by using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. MATERIALS AND METHODS: A simple and sensitive LC-MS/MS method has been developed and validated to quantify the presence of AG in plasma and various tissues of rat following oral administration of A. paniculata extract and AG in a dose of 133.33 and 100 mg/kg/day, respectively, for four weeks. RESULTS: The present study showed that the highest concentration of AG was in kidney (156.12 ng/g) followed by liver, spleen and brain while almost same concentration was found in heart and lung. The apparent C(max), T(max), elimination half-life and total exposure (AUC(0-α)) were 115.81 ng/ml, 0.75, 2.45 and 278.44 ngh/ml, respectively. CONCLUSION: This was an attempt to determine the presence of AG (a known biomarker) in tissues such as kidney, heart, lungs, brain and plasma of rats using a validated LC-MS/MS method. Furthermore, the observed reduced concentration in plasma and various tissues from 1 to 8 h might be attributed to relatively rapid elimination or distribution of AG from the central compartment.
Subject(s)
Andrographis/chemistry , Chromatography, Liquid/methods , Diterpenes/pharmacokinetics , Tandem Mass Spectrometry/methods , Administration, Oral , Animals , Area Under Curve , Diterpenes/administration & dosage , Diterpenes/isolation & purification , Dose-Response Relationship, Drug , Half-Life , India , Male , Medicine, Traditional , Rats , Rats, Wistar , Time Factors , Tissue DistributionABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The traditional healers of the Kol tribes of West Bengal, Bihar and Jharkhand (India), widely use the woody rootstock of Byttneria herbacea to reduce the swelling of limbs, due to filariasis. Besides filariasis different part of this plant is used for the treatment of cholera, diarrhoea and asthma. AIM OF THIS STUDY: This study is a preliminary attempt to evaluate the anti-oedemogenic activity of the roots of Byttneria herbacea. MATERIALS AND METHODS: The anti-oedemogenic activity of the hydroalcoholic extract of the roots of Byttneria herbacea (HBH) was evaluated against carrageenan and histamine induced rat paw oedema, acetic acid induced writhing and histamine induced vascular permeability in mice. Further, the effect of HBH on the expression of human histamine receptor type I (H1R) was studied in HeLa cells. RESULTS: HBH exhibited significant dose-dependent inhibition (*p<0.05) against carrageenan and histamine induced rat paw oedema. Similar significant dose-dependent inhibition was observed against acetic acid induced writhing and histamine-induced vascular permeability in mice. Moreover, H1R specific mRNA expression was also significantly (*p<0.05) suppressed by HBH. CONCLUSION: HBH was observed to possess anti-oedemogenic activity which is probably mediated through suppression of H1R.
