Abstract
Dosage regimen adjustments because of poor renal function are often assumed to be unnecessary for extensively metabolized antidepressants. This assumption is being increasingly questioned in recognition of the role of active drug metabolites. The purpose of this study was to assess the steady-state accumulation of the new antidepressant bupropion and its three major basic metabolites in guinea pigs, with and without experimentally-induced renal guinea pigs, with and without experimentally-induced renal failure. Two groups of guinea pigs were treated by intraperitoneal (IP) implantation of mini-osmotic pumps containing bupropion hydrochloride. Immediately after surgery, one group of animals received an injection of uranyl nitrate. After 4 days, all animals were sacrificed by decapitation following blood removal by cardiac puncture. Analysis of plasma and brain samples by high performance liquid chromatography (HPLC) for concentrations of bupropion (BUP) and its major basic metabolites, the erythro-amino alcohol (EB), the threo-amino alocohol (TB) and the hydroxy metabolite (HB) revealed greater accumulation of BUP, TB, and HB in plasma and brain of the animals with renal failure compared to controls. No difference was found between groups in the concentrations of the EB metabolite. As the guinea pig shows a BUP and metabolite plasma concentration profile similar to that seen in human studies, these results suggest that further studies of bupropion and its major metabolites are warranted in patients with impaired renal function to assess possible excessive drug and metabolite accumulation.
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References
Abram HS (1978) “Repetitive dialysis” and “Renal transplantation”. In: Thomas P Hackett and Ned H Cassem (eds) Massachusetts General Hospital Handbook of General Hospital Psychiatry, CV Mosby, St. Louis, pp 342–379
Balant L, Francis RJ, Tozer TN, Marmy A, Tschopp J-M, Fabre J (1980) Influence of renal failure on the hepatic clearance of bufuralol in man. J Biopharm Pharmacokinet 8:421–438
Bertilsson L, Mellstrom B, Sjoqvist F (1979) Pronounced inhibition of noradrenaline uptake by 10-hydroxy metabolites of nortriptyline. Life Sci 25:1285–1292
Blantz RC, Konnen K (1975) The mechanism of acute renal failure after uranyl nitrate. J Clin Invest 55:621–635
Cooper TB, Suckow, RD, Glassman A (1984) Determination of bupropion and its major basic metabolites in plasma by liquid chromatography with dual-wavelength ultraviolet detection. J Pharm Sci 73:1104–1107
Cooper TB, Perumal AS, Suckow RF, Glassman A (1985) Bupropion: possible role of major metabolites in mode of action. Clin Pharmacol Ther 37:187
Dawling S, Lynn K, Rosser R, Braithwaite R (1982) Nortriptyline metabolism in chronic renal failure: metabolite elimination. Clin Pharmacol Ther 32:322–329
DeVane CL, Jusko WJ (1981) Plasma-concentration monitoring of hydroxylated metabolites of imipramine and desipramine. Drug Intell Clin Pharm 15:263–266
Fabre LF, McLendon D (1978) Double-blind placebo controlled study of bupropion hydrochloride (Wellbutrin) in the treatment of depressed in-patients. Curr Ther Res 23:393–402
Farid FF, Wenger TL, Tsai SY, Singh BN, Stern WC (1983) Use of bupropion in patients who exhibit orthostatic hypotension on tricyclic antidepressants. J Clin Psychiatry 44: 5 (Sec 2): 170–173
Flamenbaum W, Hamburger RJ, Huddleston ML, Kaufman J, McNeil JS, Schwartz JH, Nagle R (1976) The initiation phase of experimental acute renal failure: an evaluation of uranyl nitrate-induced acute renal failure in the rat. Kidney Int 10:S115-S122
Giacomini KM, Roberts SM, Levy G (1981) Evaluation of methods for producing renal dysfunction in rats. J Pharm Sci 70:117–121
Golden RN, DeVane CL, Laizure SC, Rudorfer MV, Potter WZ (1986) Bupropion metabolites in plasma and CSF: relationship to clinical effects. Arch Gen Psychiatry (in press)
Halaris AE, Stern WC, Harto-Traux N (1981) Clinical efficacy of the new antidepressant bupropion (Wellbutrin). Psychopharmacol Bull 17:140–142
Halaris AE, Stern WC, van Wyck Fleet J, Rochelle MR (1983) Evaluation of the safety and efficacy of bupropion in depression. J Clin Psychiatry 44:(Sec 2):101–103
Jandhyala BS, Steemberg ML, Perel JM, Manian AA, Buckley JP (1977) Effect sof several antidepressants on the hemodynamics and myocardial contractility of the anesthetized dog. Eur J Pharmacol 42:403–410
Laizure SC, DeVane CL, Stewart JT, Dommissee CS, Lai AA (1985) Pharmacokinetics of bupropion and its major metabolites in normal volunteers following single dose administration. Clin Pharmacol Ther 38:586–589
Nelson JC, Bock JL, Jatlow PI (1983) Clinical implications of 2-hydroxydesipramine plasma concentrations. Clin Pharmacol Ther 33:183–189
Nizet A (1981) Influence of uranyl nitrate upon tubular reabsorption and glomerular filtration in blood perfused isolated dog kidneys. Pfluegers Arch 391:296–300
Patterson SE, Cohn VH (1984) Hepatic drug metabolism in rats with experimental chronic renal failure. Biochem Pharmacol 33:711–716
Piafsky KM, Borga O, Odar-Cederlof I, Johansson C, Sjoqvist F (1978) Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevation of plasma alpha-1-acid glycoprotein. N Engl J Med 299:1435–1438
Potter WZ, Calil HM, Manian AA, Zavadil AP, Goodwin FK (1979) Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity. Biol Psychiatry 124:601–613
Schroeder DH (1983) Metabolism and kinetics of bupropion. J Clin Psychiatry 44:(Sec 2):79–81
Sutfin TA, DeVane CL, Jusko WJ (1984) The analysis and disposition of imipramine and its active metabolites. Psychopharmacology 82:310–317
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Lindsay DeVane, C., Casey Laizure, S. & Cameron, D.F. The effect of experimentally-induced renal failure on accumulation of bupropion and its major basic metabolites in plasma and brain of guinea pigs. Psychopharmacology 89, 404–408 (1986). https://doi.org/10.1007/BF02412111
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DOI: https://doi.org/10.1007/BF02412111