Determination of betaxolol and its metabolites in blood and urine by high-performance liquid chromatography with fluorimetric detection.

Analytical methods for the determination of betaxolol and two of its metabolites in blood and urine are described. Betaxolol, alpha-hydroxybetaxolol, and the acid metabolite were extracted, with over 65% efficiency, from biological samples by liquid-liquid extraction methods. Analysis was performed using reversed-phase high-performance liquid chromatography with fluorimetric detection. N,N-Dimethyloctylamine (0.005 M) was used to improve the chromatography of betaxolol and alpha-hydroxybetaxolol, while acetic acid (1%) was used for the acid metabolite. An excitation wavelength of 200 nm was found to produce the best detector response. Linear standard curves were obtained for all three compounds with detection limits (signal-to-noise ratio = 3) varying between 1 and 10 ng/ml. The coefficients of variation of the determination for all three compounds in blood and urine varied between 3.0 and 8.7%. The metabolism of betaxolol was studied in twelve healthy male subjects. The amounts (mean +/- S.D.) of betaxolol, alpha-hydroxybetaxolol and the acid metabolite renally excreted in the first 48 h after intravenous administration of 10 mg of betaxolol hydrochloride are 17.1 +/- 6.2, 0.4 +/- 0.1 and 14.5 +/- 3.7%, respectively, of the administered dose.

Synthesis and irreversible beta-adrenergic blockade with a bromoacetamido derivative of betaxolol.

1-[4-(2-Cyclopropylmethoxyethyl)phenoxy]-3-[1-p-(bromoacetamidophe nyl) -2-methyl-2-propylamine]-2-propranol (8), which is a derivative of the beta 1-adrenergic agent betaxolol, was synthesized. Compound 8 showed less potent beta-adrenergic blocking activity than betaxolol in an in vitro test with guinea pig tracheal muscle and left atrium but retained high beta 1-selectivity. Irreversible beta-adrenoceptor antagonism of 8 was assessed by the blockade of the isoproterenol response of the guinea pig atria and by ligand binding studies with rat cerebral cortex.

Comparisons of the inotropic effects of the beta 1-adrenoceptor partial agonists SL 75.177.10 and ICI 118,587 with digoxin on the intact canine heart.

The effects of the beta 1-adrenoceptor partial agonists ICI 118,587 (xamoterol) and SL 75.177.10 on the left ventricular inotropic state and relaxation rate were compared with those of digoxin in open-chest dogs. These agents were administered to three separate groups of dogs (5, 6, and 7 dogs, respectively). In each animal, the inotropic effects were assessed at fixed heart rate (atrial pacing) and at similar end-diastolic left ventricular diameter. Under these controlled conditions, ICI 118,587 (200 micrograms/kg) increased peak (+) dP/dt by 3176 +/- 363 mm Hg/s (p less than 0.005) and the slope of the end-systolic pressure/end-systolic diameter relation rose by 190% above the control value (p less than 0.01). These changes were significantly greater than after digoxin (100 micrograms/kg) which increased these indexes, respectively, by 2132 +/- 248 mm Hg/s (p less than 0.003) and by 31 +/- 4% (p less than 0.05). SL 75.177.10 (200 micrograms/kg) also increased dP/dt, but significantly less than did digoxin or ICI 118,587 (+428 +/- 105 mm Hg/s; p less than 0.007); the increase in end-systolic pressure/diameter slope was not different from that observed after digoxin. In contrast to ICI 118,587 which accelerated isovolumic relaxation (-7.6 ms in time constant of isovolumic pressure fall; p less than 0.01), neither SL 75.177.10 nor digoxin modified this phase of the cardiac cycle. Finally, at the dose used in the study, digoxin induced ventricular arrhythmias in all animals, a side effect which was never observed after ICI 118,587 or SL 75.177.10.(ABSTRACT TRUNCATED AT 250 WORDS)