THE INTERACTION BETWEEN PROPRANOLOL AND THE NOVEL ANTIMIGRAINE AGENT ZOLMITRIPTAN (311C90)

Aims Zolmitriptan (Zomig, formerly known as 311C90), a selective 5HT(1 B/1D) agonist is under development as an acute oral treatment for migr aine, Despite the use of prophylactic medication, such as propranolol, breakthrough attacks often occur in patients. Consequently we investi gated the effects of propranolol on the pharmacokinetics of and cardio vascular responses to, zolmitriptan. Methods A double-blind, randomize d, crossover study of the effects of pre-treatment with propranolol 16 0 mg daily for 7 days or placebo on the pharmacokinetics and effects o n blood pressure of a single 10 mg dose of zolmitriptan in 12 healthy volunteers, Results Propranolol increased mean zolmitriptan C-max and AUC by 56% and 37% respectively; mean t(1/2) was prolonged from 3.1 to 4.0 h. Mean C-max and AUC of the pharmacologically active N-desmethyl metabolite were reduced by 24% and 11% respectively and the metabolit e:parent AUC ratio (AUC(m)/AUC(p)) fell from 0.46 to 0.26. Mean C-max and AUC for the inactive indole acetic acid metabolite were both reduc ed by 13% and AUC(m)/AUC(p) from 1.04 to 0.59. A small pressor effect of short duration was observed following zolmitriptan with mean peak r ises of 13 and 11 mmHg in systolic and diastolic pressures respectivel y; propranolol had no effect on the presser response, Conclusions The results suggest that propranolol inhibits biotransformation of zolmitr iptan but with no change in the small pressor response to zolmitriptan . It is therefore unlikely that the pharmacokinetic changes will lead to clinically important changes in pharmacological effects and dosage adjustment of zolmitriptan is not required in patients taking proprano lol for migraine prophylaxis.