Pharmacokinetics of bretylium in man after intravenous administration

Narang, Prem K.; Adir, Joseph; Josselson, John; Yacobi, Avraham; Sadler, John H.

doi:10.1007/bf01059384

Cited by 15 publications

(4 citation statements)

References 8 publications

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“…The elimination kinetics were consistent with a 3-compartment model with half-lives of the apparent phases of 13, 128 and 532 minutes, respectively. Renal clearance was similar to that reported in the study of Narang et al (1980). Values for the elimination half-life and renal clearance were independent of dosage.…”

Section: Intravenous Administrationsupporting

confidence: 76%

“…The volume of the central compartment is about 60L (range 26-1IOL) [Garret et aI., 1982]. The apparent volume of distribution at steady-state in the study of Narang et aL (1980) [mean 377L, range 310-466L] was slightly lower than that in the study of Garret et al (1982) [mean 251 589L, range 373-878L]. These data suggest extensive tissue binding of bretylium.…”

Section: Apparent Volume Of Distributionmentioning

confidence: 80%

“…Anderson et al (1980b) found a significantly lower renal clearance and longer half-life than in either the study of Garret et a1. (1982) or Narang et al (1980). As already pointed out, a major problem with the study of Anderson et al (1980b) was the use of 2 terminal plasma concentration values for the determination of elimination half-lives.…”

Section: Intravenous Administrationmentioning

confidence: 95%

“…In the study of Narang et al (1980), bretylium plasma concentrations declined in a biphasic manner following infusion ofbretylium tosylate 4 mg/kg. The elimination profile was consistent with a 2-compartment model, with a distribution half-life of 25 minutes and a terminal half-life on.8 hours.…”

Section: Intravenous Administrationmentioning

confidence: 96%

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Clinical Pharmacokinetics of Bretylium

Rapeport

1985

Clinical Pharmacokinetics

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Bretylium is a class III antiarrhythmic agent which is used for the management of serious and refractory ventricular tachyarrhythmias. It exhibits a complex pharmacokinetic profile which is poorly understood. The drug is poorly absorbed following oral administration, and its oral bioavailability is in the region of 18 to 23%. Peak plasma concentrations occur at 1 to 9 hours after oral ingestion, and following oral doses of 5 mg/kg average 76 ng/ml, which is 28-fold lower than those achieved after equivalent intravenous doses. Approximately 75% of a bretylium dose is absorbed within 24 hours of intramuscular administration. Peak plasma concentrations occur at 30 to 90 minutes after intramuscular administration and range from 670 to 1500 ng/ml in subjects receiving 4 mg/kg. Bretylium is negligibly bound to plasma proteins (1-6%). Although drug tissue concentrations have not been reported in humans, high values for the apparent volume of distribution suggest extensive tissue binding. In animals, bretylium is progressively taken up by the myocardium over a period of 12 hours, and at 12 hours after bolus administration, myocardial concentrations exceed plasma concentrations 6 to 12 times. It is also avidly taken up by adrenergic nerves in animals. Bretylium is almost entirely cleared by the renal route and its total body clearance is closely correlated with renal clearance. Available data suggest that bretylium exhibits a complex pharmacokinetic profile which has been described by a 3-compartment model in subjects receiving intravenous dosing. The terminal elimination half-life ranges from 7 to 11 hours following oral, intramuscular and intravenous administration, and renal clearance is about 600 ml/min after intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Intravenous Administrationsupporting

confidence: 76%

Section: Apparent Volume Of Distributionmentioning

confidence: 80%

Section: Intravenous Administrationmentioning

confidence: 95%

Section: Intravenous Administrationmentioning

confidence: 96%

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Clinical Pharmacokinetics of Bretylium

Rapeport

1985

Clinical Pharmacokinetics

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Bretylium pharmacokinetics and bioavailabilities in man with various doses and modes of administration

Garrett¹,

Green²,

Bialer³

1982

Biopharm & Drug Disp

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The pharmacokinetics and bioavailabilities of bretylium tosylate were studied in 9 male normal volunteers by 60 min constant rate intravenous infusions of 200, 300, and 400 mg, by intramuscular injection of 300 and 400 mg, by oral administration of 100, 200, and 400 mg in solution, and by oral administration of 200 mg tablets. The latter studies were repeated in the same 5 volunteers which were also studied by all modes of administration and at several doses. Intravenous studies showed a sum of 3 exponentials to characterize plasma level-time studies with a terminal half-life of 535 +/- 32 (S.E.M.) min (n = 12). The urinary recovery of unchanged drug was 77 +/- 4(S.E.M.)(n = 14). Half-lives within a subject were correlated and independent of dose. Intramuscular administration showed an apparent half-life of first-order invasion of 79 +/- 13 (S.E.M.) min (n = 6) with no apparent dose dependency and a urinary recovery of unchanged drug of 95.4 +/- 3.2 (S.E.M.) per cent with a terminal half-life similar to the intravenous studies. Oral solutions had smaller lag times of absorption [17 +/- 4(S.E.M.) min] than tablets [56 +/- 9 (S.E.M.) min] and longer apparent half-lives of first-order absorption [231 +/- 23 (S.E.M.) min] than tablets [87 +/- 15 (S.E.M.) min]. The tablets had slightly greater bioavailabilities [27 +/- 2.3 (S.E.M.) per cent] than the oral solutions [22.1 +/- 2.2 (S.E.M.) per cent] but with no apparent dose dependencies. Renal clearances were the same for all modes of administration. Means +/- S.E.M. were 735 +/- 32, i.v., 686 +/- 38, i.m., and 623 +/- 57 ml min-1, p.o. Apparent overall volumes of distribution were 589 +/- 401, i.v. and 450 +/- 671 (S.E.M.), i.m. The i.v. studies in three dogs confirmed the three-compartment body model and the high overall volumes of distribution, had terminal half-lives similar to humans and had renal clearances of 84, 164, and 207 ml min-1 that were in excess of glomerular filtration. There were no significant changes of cardiovascular parameters with the time course of the drug in the body and no significant drug-affected clinical parameters. The only consistent side effect was a generally transient nasal congestion at plasma peak time on intravenous administration.

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