Oral and intravenous bretylium disposition

Abstract

To compare the oral and intravenous disposition of bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate either orally or intravenously and crossed over 2 wk later to the opposite route (20 studies). Each experiment included sampling for drug in serum and urine over 48 hr. Bretylium tosylate was assayed by gas chromatography. Kinetic analysis provided the following mean [coefficient of variation] results: 100FPo, 22.6% [40.2%]; ClIVr, 300 ml/min [27.8%]; ClPor, 1,268 mg/min [54.8%]; ClIVB 299 ml/min [31.9%]; f, 101% [8.7%]; Vdss, 3.37 l/kg [30.5%]; λIVl, 0.0510 [12.8%]; λPGl, 0.115 [52.7%] hr−1; elimination half‐life (t½) after intravenous bretylium tosylate, 13.6 hr, and after oral bretylium tosylate, 6.0 hr (harmonic means). Bretylium tosylate binding to plasma proteins in normal volunteer samples was found to be negligible. The results indicate extensive tissue binding of bretylium tosylate. Oral doses of bretylium tosylate are only partially absorbed. Bretylium tosylate is eliminated entirely by the kidneys as unchanged drug. The greater renal clearance after oral than intravenous bretylium tosylate, and the greater elimination rate constant and shorter oral bretylium tosylate t½ are of interest but no explanation is available. Clinical Pharmacology and Therapeutics (1980) 28, 468–478; doi: © 1980 American Society for Clinical Pharmacology and Therapeutics