title: Influence of beta-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol.
abstract: OBJECTIVE
  Patients with migraine may receive the 5-HT1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other beta-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between beta-adrenoceptor blockers and rizatriptan.
  
  
  METHODS
  Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various beta-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured.
  
  
  RESULTS
  Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0, infinity) for rizatriptan by approximately 67% and the Cmax by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically significant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not significantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other significant adverse experiences during coadministration of rizatriptan with any of the beta-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other beta-adrenoceptor blockers significantly inhibited the production of the indole-acetic acid metabolite of rizatriptan and sumatriptan.
  
  
  CONCLUSIONS
  These results suggest that propranolol increases plasma concentrations of rizatriptan by inhibiting monoamine oxidase-A. When prescribing rizatriptan to migraine patients receiving propranolol for prophylaxis, the 5 mg dose of rizatriptan is recommended. Administration with other beta-adrenoceptor blockers does not require consideration of a dose adjustment.
authors.affiliation: Department of Clinical Pharmacology, Drug Metabolism and Clinical Biostatistics, Merck Research Laboratories, Blue Bell, PA 19422, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Goldberg
authors.forename: D
authors.initials: D
authors.lastname: Sciberras
authors.forename: M
authors.initials: M
authors.lastname: De Smet
authors.forename: R
authors.initials: R
authors.lastname: Lowry
authors.forename: L
authors.initials: L
authors.lastname: Tomasko
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.forename: T V
authors.initials: TV
authors.lastname: Olah
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
authors.forename: R
authors.initials: R
authors.lastname: Halpin
authors.forename: P H
authors.initials: PH
authors.lastname: Kari
authors.forename: I
authors.initials: I
authors.lastname: James
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D001682:Biological Availability; D002319:Cardiovascular System / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D008875:Middle Aged; D009248:Nadolol / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics*; D014230:Triazoles / Q000493:pharmacokinetics*; D014363:Tryptamines
chemical_list: D000319:Adrenergic beta-Antagonists; C470302:HTR1B protein, human; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D014363:Tryptamines; D009248:Nadolol; C093622:rizatriptan; D011433:Propranolol; D008790:Metoprolol