of their structural resemblance to 5-HT, the preferred substrate for MAO-A. They all have a relatively short duration of action (i.e., 2-3 hours) because of first-pass metabolic in-activation by the MAO-A into an indole acetic acid metabolite that is rapidly eliminated as their corresponding glu-curonides. Thus, the use of these triptans requires repeat dosing to prevent the recurrence of migraine attack. They are also contraindicated with concomitant use of any MAO inhibitors, especially inhibitors of MAO-A such as the anti-depressant drug, moclobemide (Aurorix, Mauerix).261,273

Eletriptan, frovatriptan, and naratriptan, on the other hand, with their 3-alkylamino side chain fused into a carbo-cyclic ring structure, all have much longer elimination half-lives and lower incidence of headache recurrence re-ported.273 This is because they are not a substrate for MAO-A (amphetamine is not a substrate for MAO because it has an additional methyl group a to the terminal amine function). These triptans are mainly degraded by the hepatic CYP isozymes (CYP1A2, 2D6, 3A4), but their bioavailability may be altered with a drug that inhibits or induces these CYP isozymes.275 For example, eletriptan is primarily metabolized by CYP3A4 isozyme, thus it is not advisable to use eletriptan with a CYP3A4 inhibitor such as ketoconazole, or nefazodone without appropriately adjusting their dosages.275

The highest reported incidences of drug-induced CNS toxicities were found with eletriptan (14% at 80-mg dose), zolmitriptan (11.5% at 5-mg dose) and rizatriptan (9.4% at 10-mg dose). They all have N-demethylated, active metabolites that can easily gain entry into the brain because of their high lipophilicity.270 Thus, the presence of this active metabolite in the brain and the high lipophilicity of the parent triptan have been suggested as a factor for contributing to the observed CNS side effects of the triptans.270 This hypothesis is further supported by the fact that frovatriptan has a much lower CNS toxicity because of the greater water solubility of its N-demethylated active metabolite that prevents it from entering the brain, whereas sumatriptan, al-motriptan, and naratriptan all have a very low reported incidence of CNS side effects because they have no clinically significant active metabolites.270,276

Donitriptan, a unique high-efficacy and high-selectivity 5-HT1B/1D agonist (i.e., with high-intrinsic activity approaching that of the endogenous agonist 5-HT) currently in late-stage clinical trials, is a novel arylpiperazole derivative with much better consistency of pain relief and a lower incidence of migraine recurrence.277 Furthermore, unlike suma-triptan, it can also block capsaicin-sensitive trigeminal sensory nerves from releasing CGRP, resulting in selective cranial vasodilatation and central nociception.278

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