AZATHIOPRINE

• Action to be taken: No action needed
• Rationale: Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phos phoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6- thioguanine nucleotides (6-TGNs) as major metabolite. Based on azathioprine metabolic pathway it is unlikely that it will interact with cannabis

CYCLOSPORINE

• Cytochrome P450 enzyme substrate: CYP3A4
• Action to be taken: Potential dose reduction. Caution and close monitoring for side effects (nephrotoxicity, hepatotoxicity, or seizures)
• Rationale: Cyclosporine is a CYP3A4 substrate. Co-administration with CYP2A4 inhibitors may decrease the metabolism and clearance of cyclosporine. This may increase serum concentrations, thus, may cause cyclosporine toxicity (e.g., nephrotoxicity, hepatotoxicity, or seizures). Reduced dosages may be required.
  

MERCAPTOPURINE

• Action to be taken: No action needed
  
• Rationale: Mercaptopurine is inactivated via two major pathways. One is thiol methylation, which is catalyzed by the polymorphic enzyme thiopurine S -methyltransferase (TPMT), to form the inactive metabolite methyl-mercaptopurine. The second inactivation pathway is oxidation, which is catalyzed by xanthine oxidase. The product of oxidation is the inactive metabolite 6- thiouric acid. Based on mercaptopurine metabolic pathway it is unlikely that it will interact with cannabis.
  

References

1. Imuran (azathioprine) package insert. Prometheus Laboratories Inc.San Diego, CA 2011
2. M S, U K. Pharmacokinetic Considerations in the Treatment of Inflammatory Bowel Disease. Clinical Pharmacokinetics. Cham: Adis International; 2001;40:723-751.
3. Neoral (cyclosporine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015
4. Purixan (mercaptopurine)package insert. Rare Disease Therapeutics, Inc. Franklin, TN, 2014