Pharmacokinetics of bethanidine in hypertensive patients

Abstract

The pharmacolinetics of bethanidine-14C was studied in three hypertensive patients. A 25-MG DOSE OF BETHANIDINE-14 C hemisulfate was administered intravenously. Plasma levels of drug were measured over the first 6 hr. In 3 to 4 days, 89% to 94% of the dose was excreted in the urine. Thin-layer chromatography (TLC) and isotope dilution analysis of the urine samples indicated that only intact bethanidine was excreted. Plasma level and urinary excretion rate profiles had miltiphasic characteristics. Estimated half-lives of the terminal phase ranged from 7 to 11 hr. Average renal clearance over the initial 6 hr approached renal plasma flow. In 2 of the patients, renal clearance between 2 and 4 hr after administration was reduced to one-helf that observed during the initial 2-hr period. After single oral administration of a 25-mg dose of bethanidine-14C hemisulfate, 48% of 61% was excreted in urine and 15% to 48% in feces. Peak urinary excretion rates were reached 6 hr following administration. The urinary excretion kinetics of bethanidine during and after repetive oral dosing was also studied. A 25-mg dose was dividied into 12 to 16 equal doses and administered avery 6 hr. A larger fraction of the cumulative dose was recovered in the urine (72% to 74%) than after the single dose, suggesting higher availability at the lower dose. Steady-state urinary excretion rates were achieved in 4 to 7 doses. The steady-state urinary excretion levels were consistent with pharmacolinetic predictions based on single oral dose data. When 2 of the patients were given imipramine for 2 days prior to an oral 25-mg dose of bethanidine-14C hemisulfate, the terminal half-lives of the urinary excretion rate profiles were shorter than those in the same patients not given imipramine.

The disposition of debrisoquine in hypertensive patients.

“…Another possibility is that absorption increases with larger doses. However, the extent of absorption of bethanidine, a related compound, decreases with dose (Shen, Gibaldi, Thorne, Ailward, Cunningham, Israili, Dayton & McNay, 1975).…”

Accumulation of debrisoquine by platelets in vivo: a model of events at the peripheral adrenergic neurone.

“…Evidence was also obtained indicating an effect of amitriptyline on the overall disposition of D. Tricyclic antidepressants are known to inhibit the metabolism of guanethidine and debrisoquine by rat liver microsomes (Mitchell, Cavanagh, Dingall & Oates, 1970) and this would be consistent with the changes in urinary recoveries of D and HD observed in our subjects. On the other hand, the elimination half-life of the related guanidinium bethanidine, which is not metabolized in man, is decreased by concomitant administration of imipramine (Shen, Gibaldi, Bellward, Cunningham, Israili, Dayton & McNay, 1975). This was explained by a decrease in the volume of distribution of bethanidine owing to antagonism of its uptake at adrenergic nerve endings, although effects of imipramine on non-specific tissue uptake and renal clearance cannot be excluded.…”

“…On the other hand, the elimination half-life of the related guanidinium bethanidine, which is not metabolized in man, is decreased by concomitant administration of imipramine (Shen, Gibaldi, Bellward, Cunningham, Israili, Dayton & McNay, 1975). This was explained by a decrease in the volume of distribution of bethanidine owing to antagonism of its uptake at adrenergic nerve endings, although effects of imipramine on non-specific tissue uptake and renal clearance cannot be excluded.…”