RESUMEN
PURPOSE: The aim of this study was to evaluate clearance from the buccal cavity and pharmacokinetic profiles of a sublingual spray formulation in the dog, to assist in interpretation of future pharmacokinetic studies. METHODS: Radiolabelled buprenorphine in a spray formulation (400 microg/100 microl in 30% ethanol) was administered sublingually to four beagle dogs, and the residence in the oral cavity was determined using gamma scintigraphy. Pharmacokinetic sampling was performed to facilitate correlation of location of dose with significant pharmacokinetic events. RESULTS: Scintigraphic imaging revealed that clearance of the formulation from the oral cavity was rapid, with a mean T 50% clearance of 0.86 +/- 0.46 min, and T 80% clearance of 2.75 +/- 1.52 min. In comparison, absorption of buprenorphine was relatively slow, with a T max of 0.56 +/- 0.13 h. Good buccal absorption despite short residence time can be explained by lipophilicity of buprenorphine enabling rapid sequestration into the oral mucosa, prior to diffusion and absorption directly into systemic circulation. CONCLUSION: This study demonstrated rapid clearance of a sublingual solution from the canine oral cavity, with T 50% similar to results previously reported in man, providing initial confidence in using a conscious dog model to achieve representative residence times for a sublingual solution.
Asunto(s)
Analgésicos Opioides/farmacología , Buprenorfina/farmacocinética , Cámaras gamma , Boca/diagnóstico por imagen , Boca/metabolismo , Absorción , Administración Sublingual , Aerosoles , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/sangre , Animales , Buprenorfina/administración & dosificación , Buprenorfina/sangre , Perros , Masculino , Mucosa Bucal/metabolismo , Cintigrafía , Reproducibilidad de los ResultadosRESUMEN
Four separate studies were conducted to examine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of eletriptan, a 5-HT(1B/1D) receptor agonist being developed for the treatment of migraines, after oral and intravenous administration. Fifty-five males received oral (1.5-30 mg or 30-120 mg) or intravenous (1.67-50 microg/kg or 50-102 microg/kg) eletriptan in four double- and single-blind, placebo-controlled, ascending-dose crossover studies. The maximum plasma concentration (Cmax) and area under the concentration curve (AUC) appeared linear over all dose ranges, with an apparent terminal half-life of 4 to 5 hours. Clearance and volume of distribution remained constant with dose. The time to first occurrence of Cmax (tmax) for oral eletriptan was approximately 1 hour and was unaffected by dose. Comparison of AUC values suggested an absolute bioavailability of approximately 50%. A linear PK/PD model, fitted to the data, predicted small, transient elevations in diastolic blood pressure following eletriptan doses > or = 60 mg. These effects were considered unlikely to be clinically significant. Eletriptan was well tolerated, and treatment-related adverse events were mild to moderate and transient. These PK properties should result in eletriptan having a rapid onset and sustained duration of action in terms of migraine efficacy.