Human pharmacokinetic and pharmacodynamic studies on Ro31-1118, a new beta-adrenoceptor antagonist.

Abstract

The pharmacokinetic and pharmacodynamic effects of Ro31‐1118 were examined in groups of healthy volunteers. In three subjects given 10 mg of [14C]‐Ro31‐1118 orally, peak levels of radioactivity (84 +/‐ 5 ng/ml) were 16 times those of the parent drug (approximately 5 ng/ml). Very little parent drug was recovered in the urine, although recovery of total radioactivity was nearly 80% in the urine by day 5. In five subjects studied after both oral and intravenous administration of 20 mg Ro31‐1118 the average bioavailability was 57% (range 41‐73%). Following intravenous infusion the apparent volume of distribution for the five subjects averaged 590 1 (range 510‐700 1). The elimination half‐life averaged 18 h (range 17‐26 h). In eight subjects who received 40, 80, 160 and 320 mg of Ro31‐1118 orally there was a linear relationship between dose and plasma concentration (r = 0.999) and between dose and AUC (r = 0.996). Ro31‐1118 had no effect on resting heart rate whereas atenolol reduced resting heart rate up to 6 h after all doses. The maximum reduction of an exercise tachycardia after Ro31‐ 1118 (320 mg) was 23.13 +/‐ 0.7% and compared with atenolol (100 mg) was 28.2 +/‐ 1.25%. At 24 h the percentage reduction after Ro31‐1118 was 21.5 +/‐ 1.7%, while after atenolol the percentage inhibition had decreased to 11.1 +/‐ 1.6%. In three subjects Ro31‐1118 (160 mg) orally had no effect on resting heart rate, forearm blood flow and systolic blood pressure, while atenolol (50 mg) reduced all three parameters.(ABSTRACT TRUNCATED AT 250 WORDS)