DULOXETINE

• Cytochrome P450 enzyme substrate: CYP2D6 and  CYP1A2
• Action to be taken: Caution and monitor for adverse effects
• Rationale: Both CYP1A2 and CYP2D6 are responsible for CYMBALTA metabolism. Co-administration of CYMBALTA with potent CYP1A2 inhibitors should be avoided. Concomitant use of CYMBALTA with potent inhibitors of CYP2D6 can result in higher concentrations of CYMBALTA.study with synthetic cannabinoids showed that synthetic cannabis may be a weak inhibitor of CYP1A2. Peginterferon alfa-2b is a CYP1A2 and CYP2D6 inhibitor. Adverse effects should be monitored associated with increased exposure to duloxetine if this is to be co-administered with peginterferon alfa-2b. Co-administration of CYMBALTA with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, should be approached with caution.  In clinical studies when duloxetine was administered in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. In vitro data showed that certain cannabinoids undergo metabolism by CYP2D6. Therefore duloxetine may result in higher serum concentrations of CBD and THC metabolites and increase chance of adverse effects of marijuana. 
  

VENLAFAXINE

• Cytochrome P450 enzyme substrate: CYP2D6 and CYP3A4
• Action to be taken: Caution with monitoring
• Rationale: Drugs that inhibit CYP2D6 may result in elevated venlafaxine plasma concentrations, particularly in patients who are CYP2D6 poor metabolizers (PMs).43 Drugs that potentially inhibit both CYP2D6 and CYP3A4 may increase the risk of venlafaxine related toxicity. 

References

1. Ashino, T. Hakukawa K, et al. Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes. The journal of toxicological sciences. Volume 39, Issue 6, Pages 815 -820, 2014
2. 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.
3. 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.​
4. Skinner MH, Kuan HY, Pan A, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003;73:170-7.
   
5. Cymbalta (duloxetine hydrochloride) package insert. Indianapolis, IN: Eli Lilly and Company; 2015 Jun.
6. Effexor (venlafaxine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals, Inc.; 2014 Jul.