AMITRIPTYLINE

• Cytochrome P450 enzyme substrate: CYP2D6, CYP2C19, CYP1A2, and CYP3A4

• Action to be taken: Caution with close monitoring. Possible dose adjustment
• Rationale: Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Co- administation of Amitriptyline with CYD2D6 inhibitors may result higher than expected plasma concentrations of amitriptyline. In vitro studies show that cannabis may be a weak inhibitor of CYO450 enzymes including CYP2D6.  Ritonavir potently inhibits CYP2D6 and CYP3A4. The inhibition of metabolism of TCA’s has been reported. The magnitude of the interaction with TCA’s is difficult to predict but may be significant. Patients are to be monitored closely; dosage adjustment may need to be made based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
  

DESPIRAMINE

• Cytochrome P450 enzyme substrate: CYP2D6

• Action to be taken: Caution with close monitoring. Possible dose adjustment with TCA serum concentration monitoring to prevent toxicity
• Rationale: Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Co- administation of despiramine with CYD2D6 inhibitors may result higher than expected plasma concentrations of despiramine. In vitro studies show that cannabis may be a weak inhibitor of CYO450 enzymes including CYP2D6.Ritonavir potently inhibits CYP2D6 and CYP3A4. The inhibition of metabolism of TCA’s has been reported. The magnitude of the interaction with TCA’s is difficult to predict but may be significant. Patients are to be monitored closely; dosage adjustment may need to be made based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
  

IMIPRAMINE

• Cytochrome P450 enzyme substrate: CYP2D6, CYP2C19, CYP1A2, and CYP3A4

• Action to be taken: Caution with close monitoring. Possible dose adjustment
• Rationale: Imipramine is extensivelly metabolized by the liver. It is N-demethylated to form active metabolite by CYP3A4, CYP2C19, and CYP1A2. Additionally imipramine and desipramine undergo hydroxylation, catalysed by CYP2D6 to form 2-
  hydroximipramine and 2-hydroxydesipramine. Fluvoxamine is a potent CYP1A2 inhibitor and a mid-level CYP2D6 inhibitor. In vitro studies have shown that cannabis may be a weak inhibitor of CYP 450 enzymes including CYP2D6 and CYP3A4. Furthermore study with synthetic cannabinoids showed that synthetic cannabis may be a weak inhibitor of CYP1A2. Therefore, based on available data the use of cannabis together with imipramine may cause exposure to increased plasma concentration of imipramine, with corresponding adverse effects. Therefore a dose adjustment may be necessary for imipramine.
  

NORTRIPTYLINE

• Cytochrome P450 enzyme substrate: CYP2D4 and CYP3A4
• Action to be taken: Caution with close monitoring. Possible dose adjustment with TCA serum concentration monitoring to prevent toxicity
• Rationale: Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. In vitro studies show that cannabis may be a weak inhibitor of CYO450 enzymes including CYP2D6. Ritonavir potently inhibits CYP2D6 and CYP3A4.The inhibition of metabolism of TCA’s has been reported. The magnitude of the interaction with TCA’s is difficult to predict but may be significant. Patients are to be monitored closely; dosage adjustment may need to be made based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
  

References

1. Amitriptyline (package insert). Sandoz Inc., Princeton, NJ 2014
2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January, 2016.
3. 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.
4. 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.​​
5. 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
6. Tofranil (imipramine) package insert. AFT Pharmaceuticals Ltd. Auckland , New Zealand 2016
7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January, 2016. Available at http://aidsinfo.nih.gov. Accessed Feb 1, 2016.
   
8.  Norvir® (Ritonavir) package insert. Chicago, IL: Abbott Laboratories; 2008