title: Clinical pharmacokinetics of intravenous and oral bretylium tosylate in survivors of ventricular tachycardia or fibrillation: clinical application of a new assay for bretylium.
abstract: We studied 12 patients receiving either chronic oral (p.o.) maintenance bretylium and/or acute intravenous (i.v.) bretylium to evaluate drug efficacy and pharmacokinetics. All patients were survivors of ventricular tachycardia or fibrillation. A new assay for bretylium was applied, and it proved sensitive and reliable. After single intravenous dosing, bretylium was eliminated from serum with a mean rate constant of lambda iv1 = 0.0515 hr-1 and a corresponding elimination half-life of tiv1/2 = 13.5 hr (7 studies), similar to previous results in normals. Total body clearance averaged 428 ml/min, of which virtually all was accounted for by renal clearance. Seven patients responding to intravenous bretylium were transferred to oral drug. During chronic therapy (mean dose, 41 mg/kg/day bretylium tosylate), mean minimum steady-state concentration of bretylium was 186 ng/ml (range, 72-461) and was accurately predicted, within experimental error, by using the elimination rate constant determined for oral, but not intravenous, drug in normal subjects (lambda po1 = 0.115 hr-1). Determination of average steady-state concentration (Css) yielded similar conclusions. Mean 24 hr urinary excretion of bretylium during oral therapy was 18.3% (range, 9-13%). These results lend validity to earlier observations in normals and suggest route and concentration dependence of disposition. Transfer to oral bretylium allowed continued control of sustained ventricular tachycardia in all 7 patients and of unsustained ventricular tachycardia in 5. Orthostatic hypotension in 4 responded to protriptyline. Six were discharged on bretylium, with a mean follow-up of 12.2 months (range, 1-25.5). Four maintained a favorable response, and 2 died suddenly at 1 and 3 months. We conclude that further evaluation or oral bretylium is justified; attempts should be made to increase steady-state concentrations during oral therapy.
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001949:Bretylium Compounds / Q000378:metabolism*; D001950:Bretylium Tosylate / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000378:metabolism
chemical_list: D001949:Bretylium Compounds; D001950:Bretylium Tosylate