The effects of moclobemide on the pharmacokinetics of the 5-HT1B/1D agonist rizatriptan in healthy volunteers

Aims The new 5-HT1B3/1D agonist rizatriptan (MK-0462) has recently been reg istered for the treatment of migraine. Its primary route of metabolism is v ia monoamine oxidase-A (MAO-A). Antidepressants such as the MAO-A inhibitor moclobemide may be used in patients with chronic headache syndromes. Hence , this study aimed to investigate the interactions between rizatriptan and moclobemide. Methods In a double-blind, randomized, placebo-controlled, two-period cross -over study 12 healthy, young volunteers (six males, six females) were trea ted with moclobemide (150 mg twice daily) or placebo for 4 days. On the fou rth day, a single dose of rizatriptan (10 mg) was administered, and subsequ ently blood and urine samples were collected for assay of rizatripan and N- monodesmethyl rizatriptan. Plasma concentrates of 3,4-dihydroxyphenylglycol (DHPG), a marker of MAO-A inhibition, were also assessed. Supine and stand ing blood pressure were measured regularly. Results Both treatments were well tolerated. During moclobemide, the increa se in supine diastolic blood pressure following rizatriptan administration was augmented. Inhibition of MAO by moclobemide was inferred from a persist ent decrease in DHPG level (43% on average). When rizatriptan was coadminis tered with moclobemide, the area under the plasma drug concentration-time p rofiles for rizatriptan and its N-monodesmethyl metabolite increased 2.2-fo ld (90% CI, 1.93-2.47) and 5.3-fold (90% CI, 4.81-5.91), respectively, when compared with placebo. Peak plasma drug concentrations for rizatriptan and its n-monodesmethyl metabolite increased 1.4-fold (90% CI-, 1.11-1.80) and 2.6-fold (90% CI, 2.23-3.14), respectively, and half-lives of both were pr olonged. Conclusions Moclobemide inhibited the metabolism of rizatriptan and its act ive N-monodesmethyl metabolite through inhibition of MAO-A. Thus, moclobemi de may considerably potentiate rizatriptan action. Concurrent administratio n of moclobemide and rizatriptan is not recommended.