The effects of moclobemide on the pharmacokinetics of the 5-HT1B/1D agonist rizatriptan in healthy volunteers.
OBJECTIVE
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.
Centre for Human Drug Research, Leiden, The Netherlands.
A D
AD
Van Haarst
J M
JM
Van Gerven
A F
AF
Cohen
M
M
De Smet
A
A
Sterrett
K L
KL
Birk
A L
AL
Fisher
M E
ME
De Puy
M R
MR
Goldberg
D G
DG
Musson
D000328:Adult; D019540:Area Under Curve; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology*; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D020912:Moclobemide; D008996:Monoamine Oxidase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D010080:Oxazoles / Q000493:pharmacokinetics; D023303:Oxazolidinones; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D018170:Sumatriptan / Q000493:pharmacokinetics; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D014363:Tryptamines
D001549:Benzamides; C470302:HTR1B protein, human; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D023303:Oxazolidinones; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D014363:Tryptamines; C089750:zolmitriptan; C093622:rizatriptan; D008734:Methoxyhydroxyphenylglycol; D018170:Sumatriptan; D020912:Moclobemide; C010117:3,4-dihydroxyphenylglycol