AMLODIPINE

• Cytochrome P450 enzyme substrate: CYP3A4
• Action to be taken: Caution with close monitoring
• Rationale:Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. In vitro studies that cannabis may be a weak inhibitor of CYP3A4, however it still may increase serum concentration of amlodipine. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A4 inhibitors.

DILTIAZEM

• Cytochrome P450 enzyme substrate: CYP3A4
• Action to be taken: Caution with close monitoring
• Rationale:Diltiazem is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a significant impact on the efficacy and side effect profile of diltiazem. In vitro studies have shown that cannabis is a substrate and weak inhibitor of CYP3A4. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood levels.

FELODIPINE

• Cytochrome P450 enzyme substrate: CYP3A4
• Action to be taken: Caution with close monitoring
• Rationale:Felodipine and cannabis are bot metabolized by cytochrome P-450 CYP3A4. Studies in healthy male volunteers showed significant alterations in the pharmacokinetics of felodipine when felodipine was administered c oncomitantly with grapefruit juice. Following the administration of a single dose of plain felodipine 5 mg tablets with 200 mL grapefruit juice or 200 mL water AUC and Cmax of felodipine increased about threefold as compared to administration with water. Coadminisration of felodipine with other drugs which follow the same route of biotransformation may result in altered bioavailability of felodipine or these drugs. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered felodipine to maintain optimum therapeutic blood levels.

NICARDIPINE

• Cytochrome P450 enzyme substrate: CYP3A4, CYP2C8, CYP2D6
• Action to be taken: Caution with close monitoring
• Rationale: Nicardipine may be metabolized mainly by human CYP2C8, CYP2D6 and CYP3A4. In vitro studies show that cannabis is mainly metabolized by CYP3A4 and CYP2C9. Furthermore cannabis may also be weak inhibitor of CYP enzymes including CYP3A4 and CYP2C.  Nicardipine is also relatively potent inhibitor of human CYP2D6, CYP3A4 and CYP2C (especially for CYP2C8 and CYP2C19) in vitro, suggesting that drug-drug interactions between nicardipine and other drugs metabolized mainly by these CYP forms could appear to occur in vivo.

VERAPAMIL

• Cytochrome P450 enzyme substrate: CYP3A4, CYP1A2, and CYP2C9
• P-gp substrate
• Action to be taken: Caution with close monitoring
• Rationale: Verapamil and cannabis are both substrates of CYP3A4. Furthermore cannabis is found to be a weak inhibitor of CYP450 enzymes including CYP3A4, and CYP2C. Grapefruit juice, an inhibitor of CYP3A4, increases AUC and peak plasma concentrations of verapamil.The half-life and renal clearance were not affected. It is recommended to avoid concomitant drug use to avoid increased drug bioavailability.
  

References

1. 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.
2. 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.​​
3. Norvasc (amlodipine) package insert. Pfizer Inc. NY, NY 2011
4. Cardizem CD (diltiazem) package insert. Biovail Laboratories International, Bridgewater NJ 2009
5. Renedil (felodipine) pacakge insert. Sanofi-aventis Canada Inc. Laval, Quebec 2006
6. Nakamura K, Ariyoshi N, Iwatsubo T, et al. Inhibitory Effects of Nicardipine to Cytochrome P450 (CYP) in Human Liver Microsomes. Biological and Pharmaceutical Bulletin. 2005;28:882-885.
7. Dahan A, Altman H. Food-drug interaction: grapefruit juice augments drug bioavailability-mechanism, extent, and relevance. Eur J Clin Nutr 2004;58:1—9.
   
8. Ho PC, Ghose K, Saville D, et al. Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers. Eur J Clin Pharmacol 2000 Dec;56:693—8.