RESUMO
The physicochemical properties, pK(a), Log P and solubility of compound alpha, (5-chloro-2-(methylthio)-6-(1-naphthyloxy)-1H-benzimidazole), a new fasciolicide agent, were characterized using conventional methods. Also, its pharmacokinetics was evaluated in sheep and cattle. In both species an oral dose of 12 mg/kg was administered. Blood samples were collected during 144 h and analyzed by using an HPLC assay. Results showed that compound alpha is a weak base with a pK(a) value of 2.87 and log P of 1.44. The solubility was very low in aqueous solvents. Pharmacokinetic studies showed that in both species compound alpha could not be detected at any sampling time. The mean half-life (t(1/2)) values of alpha sulphoxide in sheep and cattle were 19.86 and 29.87 h, while the half-life values of alpha sulphone were 19.43 and 46.32 h respectively. C(max) values of alpha sulphoxide did not differ between species while alpha sulphone values were higher in cattle. Plasma protein binding of alpha sulphoxide was between 82% and 86%. These results, combined with the previous efficacy studies, suggest that compound alpha could be a promising fasciolicide agent.
Assuntos
Antiplatelmínticos/farmacocinética , Bovinos/metabolismo , Imidazóis/farmacocinética , Naftalenos/farmacocinética , Ovinos/metabolismo , Animais , Antiplatelmínticos/sangue , Antiplatelmínticos/farmacologia , Bovinos/sangue , Cromatografia Líquida de Alta Pressão/veterinária , Fasciolidae/efeitos dos fármacos , Feminino , Meia-Vida , Imidazóis/sangue , Imidazóis/farmacologia , Masculino , Naftalenos/sangue , Naftalenos/farmacologia , Óxidos/farmacologia , Ovinos/sangue , Compostos de Enxofre/farmacologia , Dióxido de Enxofre/farmacologiaRESUMO
A method based on liquid chromatography with positive ion electrospray ionization and tandem mass spectrometry is described for the determination of terbinafine in human plasma using naftifine as internal standard. The method has a chromatographic run time of 5 minutes and was linear in the range 1.0 to 2000 ng/mL. The limit of quantification was 1.0 ng/mL; the intraday precision was 3.6%, 3.8%, 3.5%, and 4.1%; and the intraday accuracy was -2.7%, 7.7%, 4.8%, and -2.7% for 5.0, 80.0, 250.0, and 1500.0 ng/mL, respectively. The interday precision was 4.9%, 1.7%, 2.4%, and 4.6% and the interday accuracy was 0.3%, 5.8%, 6.5%, and -1.4% for the same concentrations. This method was used in a bioequivalence study of two tablet formulations of terbinafine. Twenty-four healthy volunteers (both sexes) received a single oral dose of terbinafine (250 mg) in an open, randomized, two-period crossover study. The 90% CI of geometric mean ratios between Terbinafina (Medley S/A Indústria Farmacêutica, Campinas, Brazil) and Lamisil (Novartis Biociências S/A, São Paulo, Brazil) were 90.5% to 110.0% for C max, 92.2% to 108.1% for AUC last, and 91.3% to 107.5% for AUC 0-inf. Because the 90% CI for the above-mentioned parameters were included in the 80% to 125% interval proposed by the US FDA, the two formulations were considered bioequivalent in terms of rate and extent of absorption.