DONEPEZIL

• Cytochrome P450 enzyme substrate: CYP2D6 and CYP3A4
• Action to be taken: Caution with close monitoring for side effects.
• Rationale: Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. No in vivo clinical trials have investigated the effect of ARICEPT on the clearance of drugs metabolized by CYP 3A4 or by CYP 2D6. However, in vitro studies show a low rate of binding to these enzymes that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. Based on in vitro studies, donepezil shows little or no evidence of direct inhibition of CYP2B6, CYP2C8, and CYP2C19 at clinically relevant concentrations. Population pharmacokinetic analysis showed that in the presence of concomitant CYP2D6 inhibitors donepezil AUC was increased by approximately 17% to 20% in Alzheimer’s disease patients taking ARICEPT. This represented an average effect of weak, moderate, and strong CYP2D6 inhibitors In vitro studies have shown that cannabis exhibits inhbitory action on CYP450 enzymes including CYP3A4 and CYP 2D6. Therefore based on available data concurrent administration of donepezil with cannabis should be used in caution.
  

GALANTAMINE

• Cytochrome P450 enzyme substrate: CYP2D6 and CYP3A4
• Action to be taken: Caution with close monitoring for side effects
• Rationale:  Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies indicate that cytochrome CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine, and inhibitors of both pathways increase oral bioavailability of galantamine modestly. In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found cannabinoids to be weak inhibitors of CYP enzymes. However other studies have shown that CBD is a potent inhibitor of CYP3A4 and CYP2C19 .Erythromycin, a moderate inhibitor of CYP3A4, when administered at a dose of 500 mg four times a day for 4 days, affected the AUC of galantamine minimally. Paroxetine, a strong inhibitor of CYP2D6, when administered at a dose of 20 mg/day for 16 days, increased the oral bioavailability of galantamine by about 40%. In vitro studies show that galantamine did not inhibit the metabolic pathways catalyzed by CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6 or CYP2E1. This indicates that the inhibitory potential of galantamine towards the major forms of cytochrome P450 is very low. Based on available data use of cannabis and galantamine should be used in caution.
  

RIVASTIGMINE

• Action to be taken: No action needed
• Rationale: Rivastigmine is rapidly and extensively metabolized, primarily via cholinesterase - mediated hydrolysis to the
  decarbamylated metabolite. Based on evidence from in vitro and animal studies, the major cytochrome P450 isozymes are minimally involved in rivastigmine metabolism. Consistent with these observations is the finding that no drug interactions related to cytochrome P450 have been observed in humans. Therefore based on available data drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine.
  

References

1. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety. Life Sciences. 2011;88:730-736.
2. JIANG R, YAMAORI S, OKAMOTO Y, YAMAMOTO I, WATANABE K. Cannabidiol Is a Potent Inhibitor of the Catalytic Activity of Cytochrome P450 2C19. Drug Metabolism and Pharmacokinetics. 2013;28:332-338.
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. Aricept (donepezil) package insert. Eisai Inc., Woodcliff Lake, NJ 2016
   
6. Exelon (rivastigmine) package insert. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 2016
7. Razadyne (galantamine)package insert. Janssen Pharmaceuticals, Inc. Titusville, NJ