Background/Aims: The study aimed at investigating the effects of multiple-dose bupropion (potent inhibitor of CYP2D6) on the pharmacokinetics (PKs) of single-dose nebivolol (CYP2D6 substrate) and to evaluate the clinical relevance of this potential drug interaction. Methods: This open-label, nonrandomized clinical study had a 2-period design: during period 1 (reference), a single dose of 5 mg nebivolol was administered, while during period 2 (test), 5 mg nebivolol + 300 mg bupropion were ingested concomitantly, after a pretreatment regimen with bupropion (7 days). The PK parameters of nebivolol and its active metabolite were analyzed by noncompartmental modeling, while the pharmacodynamic (PD) parameters (blood pressure and heart rate) were assessed at rest. Results: Bupropion plus nebivolol increased the mean peak plasma concentrations (Cmax) of nebivolol (1.67 ± 0.69 vs. 3.80 ± 1.70 ng/ml) and its active metabolite (0.68 ± 0.22 vs. 1.13 ± 0.38 ng/ml) compared to nebivolol alone. After bupropion pretreatment, the exposure to nebivolol was increased by 7.2-fold for the parent drug and 4-fold for the hydroxylated active metabolite. The difference between the PD parameters measured during the 2 periods was not significant. Conclusion: The study concluded that bupropion influenced the PKs of nebivolol in healthy volunteers, but a clinical relevance was not established. However, this latter aspect requires further investigation.

Gray CL, Ndefo UA: Nebivolol: a new antihypertensive agent. Am J Health Syst Pharm 2008;65:1125-1133.
Baldwin CM, Keam SJ: Nebivolol: in the treatment of hypertension in the US. Am J Cardiovasc Drugs 2009;9:253-260.
Kamp O, Metra M, Bugatti S, Bettari L, Dei Cas A, Petrini N, Dei Cas L: Nebivolol: haemodynamic effects and clinical significance of combined beta-blockade and nitric oxide release. Drugs 2010;70:41-56.
Sahana GN, Sarala N, Kumar TN: Nebivolol - pharmacological aspects. Int J Biol Med Res 2011;2:577-580.
Moen MD, Wagstaff AJ: Nebivolol: a review of its use in the management of hypertension and chronic heart failure. Drugs 2006;66:1389-1409; discussion 1410.
Howlett JG: Nebivolol: vasodilator properties and evidence for relevance in treatment of cardiovascular disease. Can J Cardiol 2014;30(5 suppl):S29-S37.
McNeely W, Goa KL: Nebivolol in the management of essential hypertension: a review. Drugs 1999;57:633-651.
Weber MA: The role of the new beta-blockers in treating cardiovascular disease. Am J Hypertens 2005;18(12 pt 2):169S-176S.
Gupta S, Wright HM: Nebivolol: a highly selective beta1-adrenergic receptor blocker that causes vasodilation by increasing nitric oxide. Cardiovasc Ther 2008;26:189-202.
Bristow MR, Nelson P, Minobe W, Johnson C: Characterization of β1-adrenergic receptor selectivity of nebivolol and various other beta-blockers in human myocardium. Am J Hyperten 2005;18:A51-A52.
Cockcroft J: A review of the safety and efficacy of nebivolol in the mildly hypertensive patient. Vasc Health Risk Manag 2007;3:909-917.
Brixius K, Bundkirchen A, Bölck B, Mehlhorn U, Schwinger RH: Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium. Br J Pharmacol 2001;133:1330-1338.
Gielen W, Cleophas TJ, Agrawal R: Nebivolol: a review of its clinical and pharmacological characteristics. Int J Clin Pharmacol Ther 2006;44:344-357.
Weiss R: Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation. Vasc Health Risk Manag 2006;2:303-308.
Jefferson JW, Pradko JF, Muir KT: Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Ther 2005;27:1685-1695.
Spina E, Trifirò G, Caraci F: Clinically significant drug interactions with newer antidepressants. CNS Drugs 2012;26:39-67.
Wilkes S: The use of bupropion SR in cigarette smoking cessation. Int J Chron Obstruct Pulmon Dis 2008;3:45-53.
Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT: Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev 2006;12:178-207.
Saiz Ruiz J, Gibert J, Gutiérrez Fraile M, Bobes J, Vallejo J, Iglesias C, Iriarte V: Bupropion: efficacy and safety in the treatment of depression. Actas Esp Psiquiatr 2011;39(suppl 1):1-25.
Spina E, Santoro V, D'Arrigo C: Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther 2008;30:1206-1227.
Dhillon S, Yang LP, Curran MP: Bupropion: a review of its use in the management of major depressive disorder. Drugs 2008;68:653-689.
Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, Adson DE: Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol 2005;25:226-229.
Dimos AK, Stougiannos PN, Kakkavas AT, Trikas AG: Depression and heart failure. Hellenic J Cardiol 2009;50:410-417.
Khan S, Khan A, Ghaffar R, Awan ZA: Frequency of depression in patients with chronic heart failure. J Ayub Med Coll Abbottabad 2012;24:26-29.
Scalco AZ, Scalco MZ, Azul JB, Lotufo Neto F: Hypertension and depression. Clinics (Sao Paulo) 2005;60:241-250.
Lindamood C, Ortiz S, Shaw A, Rackley R, Gorski JC: Effects of commonly administered agents and genetics on nebivolol pharmacokinetics: drug-drug interaction studies. J Clin Pharmacol 2011;51:575-585.
Briciu C, Neag M, Muntean D, Vlase L, Bocsan C, Buzoianu A, Gheldiu AM, Achim M, Popa A: A pharmacokinetic drug interaction study between nebivolol and paroxetine in healthy volunteers. J Clin Pharm Ther 2014;39:535-540.
Briciu C, Neag M, Muntean D, Vlase L, Bocsan C, Buzoianu A, Gheldiu AM, Achim M, Popa A: A pharmacokinetic drug interaction study between nebivolol and duloxetine. Exp Clin Cardiol 2014;20:1374-1379.
Kamali F, Howes A, Thomas SH, Ford GA, Snoeck E: A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine. Br J Clin Pharmacol 1997;43:201-204.
McCollum DL, Greene JL, McGuire DK: Severe sinus bradycardia after initiation of bupropion therapy: a probable drug-drug interaction with metoprolol. Cardiovasc Drugs Ther 2004;18:329-330.
Moody DE, Backman RL: Metoprolol and bupropion interaction: a case study. Clin Exp Pharmacol 2014;4:165.
De Crée J, Geukens H, Cobo C, Verhaegen H: Subacute hemodynamic effects of nebivolol in man at rest and during exercise. Angiology 1987;38:440-448.
Zanchetti A: Clinical pharmacodynamics of nebivolol: new evidence of nitric oxide-mediated vasodilating activity and peculiar haemodynamic properties in hypertensive patients. Blood Press Suppl 2004;1:17-32.
Münzel T, Gori T: Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol 2009;54:1491-1499.
Van Nueten L, De Crée J: Nebivolol: comparison of the effects of dl-nebivolol, d-nebivolol, l-nebivolol, atenolol, and placebo on exercise-induced increases in heart rate and systolic blood pressure. Cardiovasc Drugs Ther 1998;12:339-344.
Badar VA, Hiware SK, Shrivastava MP, Thawani VR, Hardas MM: Comparison of nebivolol and atenolol on blood pressure, blood sugar, and lipid profile in patients of essential hypertension. Indian J Pharmacol 2011;43:437-440.
Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ: Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis. Circulation 2014;129:28-41.
Sharma A, Thakar S, Lavie CJ, Garg J, Krishnamoorthy P, Sochor O, Arbab-Zadeh A, Lichstein E: Cardiovascular adverse events associated with smoking-cessation pharmacotherapies. Curr Cardiol Rep 2015;17:554.
Fernandez A, Bang SE, Srivathsan K, Vieweg WV: Cardiovascular side effects of newer antidepressants. Anadolu Kardiyol Derg 2007;7:305-309.
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