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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.