Influence of beta-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol

Aims 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 migrai ne prophylaxis. The present studies investigated the potential for pharmaco kinetic or pharmacodynamic interaction between beta -adrenoceptor blockers and rizatriptan. Methods Four double-blind, placebo-controlled, randomized crossover investi gations were performed in a total of 51 healthy subjects. A single 10 mg do se of rizatriptan was administered after 7 days' administration of proprano lol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (1 00 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various beta -adre noceptor blockers were performed in human S9 fraction. Production of the in dole-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 C-max by approximately 75%. A reduction in the do se of propranolol (60 mg twice daily) and/or the incorporation of a delay ( 1 or 2 h) between propranolol and rizatriptan administration did not produc e a statistically significant change in the effect of propranolol on rizatr iptan 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 advers e experiences attributable to the pharmacokinetic interaction between propr anolol and rizatriptan were observed, and no subjects developed serious cli nical, laboratory, or other significant adverse experiences during coadmini stration of rizatriptan with any of the beta -adrenoceptor blockers. In vit ro incubations showed that propranolol, but not other beta -adrenoceptor bl ockers significantly inhibited the production of the indole-acetic acid met abolite of rizatriptan and sumatriptan. Conclusions These results suggest that propranolol increases plasma concent rations 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 -a drenoceptor blockers does not require consideration of a dose adjustment.