Ro 3-3528, a ?-adrenoceptor blocking agent: Oral and intravenous pharmacokinetic studies in normal volunteers

Abstract

Plasma levels of Ro 3-3528 have been measured fluorimetrically in man following oral and intravenous administration. Peak plasma levels, and the time at which peak was reached, varied widely between fasting subjects following oral administration, but identical dosage repeated in an individual produced comparable results. The mean half-life of Ro 3-3528 orally was 2.31 h (S.D.±0.35): after intravenous administration there was a biexponential fall in plasma levels; the early phase with a half-life of five minutes consistent with rapid redistribution of Ro 3-3528 from plasma to other tissue compartments, and a late phase with a mean half-life of 2.42 h (S.D.±0.33) representing concurrent metabolism and excretion. The effect of Ro 3-3528 on exercise tachycardia in normal volunteers was assayed against that of propranolol and of placebo by oral and intravenous routes. Dose dependent inhibition of exercise tachycardia was shown for both drugs by each route of administration. The dose ratio of propranolol to Ro 3-3528 was 1:3.5—6 orally and 1:5—6 intravenously. The effect of exercise on the volume of distribution of drugs is discussed. The use of a multivariate analysis in evaluation of pharmacokinetic studies is considered.