Disposition of bretylium in man and rat; A sensitive chemical method for its estimation in plasma and urine

Abstract

A gas chromatographic method is described which allows estimation of bretylium, a quarternary ammonium compound, in plasma and urine at drug concentrations as low as 0.07 fig per milliliter. This sensitivity allows the measurement of plasma levels of bretylium in patients receiving therapeutic doses. The plasma level of bretylium in man does not decrease as a first-order function. During the first 24 hours after drug administration the half-life increased from 1 to 5.5 hours. In man, 70 to 80 per cent of an intramuscular dose of bretylium was excreted unchanged in the urine within 24 hours and an additional 10 per cent was excreted during the next 3 days. In the rat, 63 per cent of an intramuscular dose was excreted unchanged in the urine; 31 per cent was excreted unchanged in the feces. Excretion into the bile probably accounts for the bretylium found in rat feces.

Uptake and Retention of 14C‐Bretylium in Degenerating Postganglionic Sympathetic Nerves of the Rat

“…Bretylium is known to accumulate in normal adrenergic nerves of the cat (BOURA et al 1960) and the rat (NAMM et al 1975). In the rat bretylium is not metabolized to any appreciable extent as 94 per cent of an administered dose was found to be excreted in unchanged form in the urine and bile within 4 days (KUNTZMAN et al 1970). Thus, in the present study, in which ''C-labelled bretylium was used, the amount of radioactivity found in the various organs was taken as a measure of the bretylium content.…”

GLC determination of bretylium in biological fluids

“…Bretylium, a quaternary ammonium compound, can be extracted from biological samples by an ion-pair extraction procedure, a complicated and tedious method described previously (6). In the present study, the use of acetonitrile as a deproteinization agent served to remove the proteins, to purify the biological sample, and to enhance the partitioning of bretylium into methylene dichloride, which was used as the extraction solvent.…”

“…Various methods for its determination have been reported (3-7). The most promising method is a GLC analysis (6) utilizing sodium thiophenolate to react with bretylium to produce o-bromobenzyl phenylthio ether. However, it is tedious and lacks sufficient sensitivity.…”

“…Sodium 2,4,5-trichlorothiophenolate (IV) was used as a reacting agent. It was synthesized by a method similar to that described previously for Genes Chemical Co., New York, N.Y. the preparation of sodium thiophenolate (6,8). The reagent was only moderately hygroscopic and, when stored in a drying oven, was stable for a t least 6 months.…”

Tissue Distribution of [14C]Bretylium Tosylate in Rats

“…An average of 94-95% of a 10-mg/kg [14C]bretylium tosylate dose was recovered in 72 hr, of which 63-6596 was excreted unchanged in urine and 3631% was eliminated unchanged in feces following intravenous administration, indicating a pronounced biliary excretion (7,8). The purpose of the present investigation was to examine the distribution pattern of bretylium in well-perfused organs, heart, kidney, and liver, which are the sites of pharmacological action, urinary excretion, and possible metabolism of the drug, respectively, in rats.…”