MIRTAZAPINE
TIZANIDINE
- Cytochrome P450 enzyme substrate: CYP1A2, CYP2D6, CYP3A4
- Action to be taken: Caution monitor therapy.
- Rationale: In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8 hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. In vitro studies have shown that cannabis undergoes major metabolism by CYP3A4 and CYP2C19 and minor metabolism by CYP2D6. Additionally studies have found that CBD is a potent inhibitor of CYP3A4. Cimetidine, a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, given at 800 mg b.i.d. at steady state was coadmini stered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased more than 50%. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started, or increased when cimetidine treatment is discontinued. Coadministration of the potent CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) incr eased the peak plasma levels and the AUC of a single 30-mg dose of mirtazapine by approximately 40% and 50%, respectively.
TIZANIDINE
- Cytochrome P450 enzyme substrate: CYP1A2
- Action to be taken: Caution monitor therapy.
- Rationale: Tizanidine is primarily metabolized by CYP1A2. Tizanidine clearance is significantly reduced by co-administration of potent inhibitors of CYP1A2. Various studies with cannabis smoke and with synthetic cannabis have shown that cannabis has weak inhibitory action at CYP1A2. Based on available data, caution should be used when cannabis is co-administered with tizanidine, as increased tizanidine concentrations can lead to oversedation, significant hypotension, potential liver problems, and other events.
References
- 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.
- Zanaflex (tizanidine) tablets package insert. Hawthorne, NY: Acorda Therapeutics, Inc.; 2013
- Remeron (mirtazapine) tablets package insert. N.V. Organon, Oss, The Netherlands 2007