Oral and intravenous bretylium disposition

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Abstract
To compare the oral and i.v. disposition of [the antiarrhythmic] bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate orally or i.v. and crossed over 2 wk later to the opposite route (20 studies). Each experiment included sampling for drug in serum and urine over 48 h. Bretylium tosylate was assayed by gas chromatography. Kinetic analysis provided the following mean [coefficient of variation] results: 100FPo [percent of dose reaching circulation unchanged after oral administration], 22.6% [40.2%]; ClrIV [renal clearance of drug after i.v. administration], 300 ml/min [27.8%]; ClrPo [renal clearance of drug after oral administration], 1268 mg/min [54.8%]; ClBIV [total body clearance of drug after i.v. administration], 229 ml/min [31.9%]; f [fraction of drug reaching circulation that is ultimately excreted unchanged in the urine], 101% [8.7%]; Vdss [steady-state volume distribution], 3.37 l/kg [30.5%]; .lambda.lIV [apparent elimination rate constant after i.v. administration], 0.0510 [12.8%]; .lambda.lPo [apparent elimination rate constant after oral administration], 0.115 [52.7%]/h; elimination half-life (t1/2) after i.v. bretylium tosylate, 13.6 h and after oral bretylium tosylate, 6.0 h (harmonic means). Bretylium tosylate binding to plasma proteins in normal volunteer samples was negligible. Extensive tissue binding of bretylium tosylate is indicated. 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 i.v. bretylium tosylate and the greater elimination rate constant and shorter oral bretylium tosylate t1/2 are of interest, but no explanation is available.

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