Influence of beta-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol
Mr. Goldberg et al., Influence of beta-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol, BR J CL PH, 52(1), 2001, pp. 69-76
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.