Influence of β‐adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5‐HT_1B/1D agonist: differential effects of propranolol, nadolol and metoprolol

Abstract

Aims Patients with migraine may receive the 5-HT 1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other b-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between b-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 b-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,?) for rizatriptan by approximately 67% and the C max 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 signi®cant 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 signi®cantly 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 signi®cant adverse experiences during coadministration of rizatriptan with any of the b-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other b-adrenoceptor blockers signi®cantly 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 b-adrenoceptor blockers does not require consideration of a dose adjustment.

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

“…Rizatriptan is mainly metabolized by MAO-A via oxidative deamination [525]. Propranolol, but not metoprolol and nadolol, increased its AUC by 70% through MAO-A inhibition [526]. In vitro studies showed that propranolol, but not metoprolol and nadolol, significantly inhibited the production of the indole-acetic acid metabolite of rizatriptan and sumatriptan.…”

Triptan efficacy in migraine attacks: from appropriate diagnosis to metabolic profiles and pharmacogenomics

“…Having multiple routes for metabolism is an advantage since there are alternative metabolic pathways with in-built redundancy, so if one pathway is non-functional, others can take over to ensure the effectiveness of the drug as well as avoiding drug accumulation (and therefore adverse events) by fast production of inactive metabolites. Drugs with single dominant metabolic pathways are also more likely to interact with other drugs metabolised by the same pathway, as seen in the case of the necessity of lowering the dose of rizatriptan in migraine patients also receiving preventive treatment with propranolol [Goldberg et al, 2001].…”

Medication overuse and chronic migraine: a critical review according to clinical pharmacology

“…Inhibition of rizatriptan metabolism since both drugs are metabolized by MAO-A and compete with each other Dose of rizatriptan should be reduced to 5 mg; maximum 15 mg/day [127] Rizatriptan, zolmitriptan, sumatriptan/MAO inhibitors Increased risk of triptan adverse reactions…”