- Cytochrome P450 enzyme substrate: CYP3A4 and CYP2D6
- Action to be taken: Caution with close monitoring. Potential dose reduction
- Rationale: In vitro studies have shown that cannabis is a weak inhibitor of CYP450 enzymes including CYP3A4 and CYP2D6. Ritonavir, a potent CYP3A4 inhibitor, may increase systemic exposure of almotriptan. The recommended starting dose of almotriptan is 6.25 mg; this should not exceed 12.5 mg within a 24 hour period. Co-administration with CYP3A4 inhibitors should be avoided in patients with renal or hepatic impairment. In a drug interaction study, co-administration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in approximately 60% increase in almotriptan exposure.
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Caution with close monitoring
- Rationale: Eletriptan is metabolized via CYP3A4. In vitro studies have shown that cannabis is a weak inhibitor of CYP450 enzymes including CYP3A4 .Grapefruit juice inhibits CYP3A4 in enterocytes. It is not clear what effect this has on eletriptan bioavailability or metabolism. Patients are advised to not alter CYP3A4 inhibitor intake while on eletriptan. The clinical significance of the potential interaction is currently unknown.
- Cytochrome P450 enzyme substrate: CYP1A2
- Action to be taken: No action needed
- Rationale: Frovatriptan is a substrate of CYP1A2; however clinically significant interactions with CYP1A2 inhibitors are not likely due to its’ wide therapeutic range in addition to its partial renal elimination.
- Cytochrome P450 enzyme substrate: CYP3A4, CYP2D6
- Action to be taken: Caution
- Rationale: Naratriptan is predominantly eliminated in urine, with 50% of the dose recovered unchanged and 30% as metabolites in urine. In vitro, naratriptan is metabolized by a wide range of cytochrome P450 isoenzymes into a number of inactive metabolites. Cannabis is a weak inhibitor of CYP450 enzymes and thus may effect how naratriptan is metabolized. Therefore based on available data patients should be monitored for possible side effects of naratriptan including symptoms of serotonin syndrome.
- Action to be taken: No action needed
- Rationale: In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme, and inhibitors of that enzyme may alter sumatriptan pharmacokinetics to increase systemic exposure Data shows that CYP450 enzymes are not involved in metabolism of sumatriptan.
- Cytochrome P450 enzyme substrate: CYP1A2 and CYP3A4
- Action to be taken: Caution with close monitoring for adverse effects
- Rationale: Zolmitriptan is a substrate of CYP3A4. Cannabis is also a substrate for CYP3A4 and exhibits a weak inhibition at this enzyme. Clinical monitoring for adverse effects is recommended during co-administration with CYP3A4 inhibitors, since there is a potential for elevated zolmitriptan concentrations.
- Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
- Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.
- Yu A-M. Indolealkylamines: Biotransformations and Potential Drug–Drug Interactions. The AAPS Journal. 2008;10(2):242. doi:10.1208/s12248-008-9028-5.
- Axert (almotriptan) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2014 Aug.
- Relpax (eletriptan hydrobromide) package insert. New York, NY: Pfizer Inc.; 2007 Apr.
- Frova (frovatriptan) package insert. Chadds Ford, PA: Endo Pharmaceuticals, Inc.; 2013 Oct.
- Dixon C. M., Park G. R., Tarbit M. H. Characterization of the enzyme responsible for the metabolism of sumatriptan in human liver. Biochem. Pharmacol. 1994;47(7):1253–1257. doi: 10.1016/0006-2952(94)90397-2
- Lionetto L, Casolla B, Mastropietri F, et al. Pharmacokinetic evaluation of zolmitriptan for the treatment of migraines. Expert Opin Drug Metab Toxicol 2012;8:1043-50.
- Imitrex (sumatriptan) package insert. GlaxoSmithKline, Research Triangle Park, NC