ABSTRACT
AIMS: The new 5-HT1B/1D agonist rizatriptan (MK-0462) has recently been registered for the treatment of migraine. Its primary route of metabolism is via 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 treated with moclobemide (150 mg twice daily) or placebo for 4 days. On the fourth day, a single dose of rizatriptan (10 mg) was administered, and subsequently 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 standing blood pressure were measured regularly. RESULTS: Both treatments were well tolerated. During moclobemide, the increase in supine diastolic blood pressure following rizatriptan administration was augmented. Inhibition of MAO by moclobemide was inferred from a persistent decrease in DHPG level (43% on average). When rizatriptan was coadministered with moclobemide, the area under the plasma drug concentration-time profiles for rizatriptan and its N-monodesmethyl metabolite increased 2.2-fold (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 prolonged. CONCLUSIONS: Moclobemide inhibited the metabolism of rizatriptan and its active N-monodesmethyl metabolite through inhibition of MAO-A. Thus, moclobemide may considerably potentiate rizatriptan action. Concurrent administration of moclobemide and rizatriptan is not recommended.
Subject(s)
Benzamides/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Oxazolidinones , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacokinetics , Triazoles/pharmacokinetics , Adult , Area Under Curve , Benzamides/adverse effects , Biotransformation , Blood Pressure/drug effects , Cross-Over Studies , Double-Blind Method , Female , Half-Life , Humans , Male , Methoxyhydroxyphenylglycol/analogs & derivatives , Methoxyhydroxyphenylglycol/blood , Methoxyhydroxyphenylglycol/metabolism , Moclobemide , Monoamine Oxidase Inhibitors/adverse effects , Oxazoles/pharmacokinetics , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Serotonin Receptor Agonists/adverse effects , Sumatriptan/pharmacokinetics , Triazoles/adverse effects , TryptaminesABSTRACT
Rizatriptan is a potent, oral 5-HT(1B/1D) agonist with a rapid onset of action being investigated for the acute treatment of migraine. This study examined the clinical and pharmacolinetic interaction between rizatriptan and the selective serotonin reuptake inhibitor, paroxetine. In this two-period crossover study, 12 healthy young subjects (6 males and 6 females) received 1 mg rizatriptan following 14 days of treatment with placebo or paroxetine (20 mg once daily). Plasma was sampled for rizatriptan and N-monodesmethyl rizatriptan, a minor but active metabolite of rizatriptan. Safety evaluations included monitoring for adverse events, vital signs, and visual analog scale assessment of mood. Plasma levels of rizatriptan and N-monodesmethyl rizatriptan were not altered when rizatriptan was administered with paroxetine compared to the placebo. Clinically, coadministration of rizatriptan with paroxetine was well tolerated. Blood pressure, heart rate, and temperature changes during the observation period did not differ to a clinically significant degree when rizatriptan was administered with paroxetine compared to the placebo. No effects on mood occurred following treatment with the combination compared to rizatriptan alone. Adverse events following rizatriptan administration with paroxetine were similar to those reported when rizatriptan was given with the placebo.
