RESUMEN
The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49 465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49 465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49 465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49 465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60 degrees head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49 465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.
Asunto(s)
Hemodinámica/efectos de los fármacos , Quinolinas/metabolismo , Quinolonas , Vasodilatadores/metabolismo , Administración Oral , Adulto , Presión Sanguínea/efectos de los fármacos , Diuresis/efectos de los fármacos , Método Doble Ciego , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Cinética , Masculino , Quinolinas/efectos adversos , Quinolinas/farmacología , Distribución Aleatoria , Renina/sangre , Saliva/metabolismo , Vasodilatadores/efectos adversos , Vasodilatadores/farmacologíaRESUMEN
A method is described for the measurement of the antidepressant drug dothiepin in human plasma. The procedure involves the addition of deuterodothiepin as an internal standard, extraction and measurement by chemical ionisation mass fragmentography. The minimum measurable concentration of 0.5 ng/ml enabled the pharmacokinetics of dothiepin in man to be studied after a single oral dose of 75 mg of dothiepin hydrochloride. Unlike other tricyclic antidepressants the apparent half-life of elimination (approximately 24 h) showed very little intersubject variation. However, the apparent volume of distribution was much more variable and could account for the wide range of steady state concentrations which have been found in patients taking dothiepin.
Asunto(s)
Dibenzotiepinas/sangre , Dotiepina/sangre , Cromatografía de Gases y Espectrometría de Masas/métodos , Administración Oral , Adulto , Dotiepina/administración & dosificación , Humanos , MasculinoAsunto(s)
Dibenzotiepinas/metabolismo , Dotiepina/metabolismo , Animales , Biotransformación , Gatos , Perros , Haplorrinos , Humanos , Técnicas In Vitro , Hígado/metabolismo , Papio , Conejos , Ratas , Especificidad de la EspecieRESUMEN
Flurbiprofen was rapidly absorbed in all species studied. 2. Half-lives of elimination measured 0 to 12 h after a single dose were: mouse 3.4 h, rat 2.5 h, dog 10.1 h, baboon 3.1 h and man 3.9 h. A second phase of elimination was seen in the dog. Flurbiprofen accumulated in the circulation of the dog on repeated dosing. 3. After dosing with [14C]flurbiprofen, tissue levels of radioactivity in dog and baboon were similar to that in plasma. In the rat, levels were slightly elevated in liver, kidney, large intestine and thyroid after repeated dosing. 4. The dog excreted equal amounts of radioactivity in urine and faeces. In other species renal excretion was the more important route. 5. Six metabolites have been detected, the most important being: 2-(2-fluoro-4'-hydroxy-4-biphenylyl)propionic acid (metabolite 1), 2-(i-fluoro-3',4'-dihydroxy-4-biphenylyl)propionic acid (metabolite 2) and 2-(2-fluoro-3'-hydroxy-4'-methoxy-4-biphenylyl)propionic acid (metabolite 3). The proportions of the metabolites and the extents of their conjugation varied among the species. 6. Metabolites were detected in the circulation of rat, mouse and baboon but not in dog and man. 7. Flurbiprofen did not affect the hepatic drug-metabolizing enzyme system of rat. 8. Flurbiprofen was extensively bound to serum protein of rat, dog, baboon and man.
Asunto(s)
Flurbiprofeno/metabolismo , Propionatos/metabolismo , Adolescente , Adulto , Animales , Bilis/metabolismo , Proteínas Sanguíneas/metabolismo , Perros , Circulación Enterohepática , Femenino , Flurbiprofeno/sangre , Flurbiprofeno/farmacología , Haplorrinos , Humanos , Absorción Intestinal , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Papio , Pentobarbital/metabolismo , Pentobarbital/farmacología , Unión Proteica , Ratas , Distribución TisularRESUMEN
A method has been developed for the separation and measurement of dothiepin and the N-demethyl metabolites, northiaden, in human plasma or serum by high performance liquid chromatography. The method uses a structurally-related drug, amitriptyline, as an internal standard and provides a limit of detection of about 10 ng/ml for each component. At a concentration of 20 ng/ml, northiaden and dothiepin could be measured with +/-11% and +/- 6% of the mean respectively and at 200 ng/ml within +/-3% and 1% of the mean. The method has been applied to the analysis of serum from patients undergoing dothiepin therapy.