The pharmacokinetics and haemodynamics of BTS 49465 and its major metabolite in healthy volunteers

Abstract

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.

A comparison of the effects of flosequinan, a new vasodilator, and propranolol on sub‐maximal exercise in healthy volunteers.

“…The interval between study days was thus 14 days, which is adequate for 95% elimination of the major metabolite of flosequinan (Wynne et al, 1985).…”

“…In addition studies in patients with severe congestive heart failure have shown that a single oral dose reduces resting left ventricular filling pressure and systemic vascular resistance (Kessler & Packer, 1987 given to patients in heart failure refractory to diuretics (Elborn et al, 1988). In relation to blood pressure flosequinan produces a fall in both systolic and diastolic pressures in healthy volunteers (Wynne et al, 1985) and patients with untreated moderate essential hypertension (Thien et al, 1987). Further studies are now required to determine its place in the management of hypertension.…”

Acute and chronic effects of flosequinan on resting and exercise haemodynamics in congestive heart failure

“…Flosequinan (7-fluoro-1-methyl-3-methyl-sulphinyl-4-quinolone) is a vasodilator which is active in both veins and arteries [10,11]. It has a hypotensive action [11,12] and, in patients with congestive heart failure, it has been shown to decrease resting preload and afterload while improving cardiac performance [13][14][15].…”

“…It has a hypotensive action [11,12] and, in patients with congestive heart failure, it has been shown to decrease resting preload and afterload while improving cardiac performance [13][14][15]. In patients with congestive heart failure following acute myocardial infarction, the peak haemodynamic effect was observed at 1-2 h post dose [16] with persistent effects over the 4 h post-dose study period.…”

Studies on the cardiac actions of flosequinan in vitro

“…Yates & Hicks, 1988;Falotico et al, 1989;Greenberg & Touhey, 1990) which may have clinical relevance. Clinical studies have shown that flosequinan has an active sulphone metabolite, BTS 53554, which probably contributes to the overall haemodynamic response in man following oral administration (Wynne et al, 1985).…”