Amitriptyline is metabolized by the liver to inactive metabolites. The protein in the liver responsible for the majority of this metabolism is the cytochrome p450 enzyme CYP2C19 (pronounced "sip two see nineteen"). Amitriptyline is also metabolized in the liver to another active form, nortriptyline, by the cytochrome p450 enzyme CYP2D6 (pronounced "sip two dee six"). Nortriptyline is further metabolized by the liver to inactive metabolites via CYP2D6.

Across populations, CYP2C19 and CYP2D6 protein alleles can have different genetic variants that impact their ability to metabolize amitriptyline and nortriptyline. The different CYP2C19 alleles can produce five different metabolism phenotypes: ultrarapid, rapid, normal, intermediate, and poor metabolism. The different CYP2D6 alleles can produce four different metabolism phenotypes: ultrarapid, normal, intermediate, and poor metabolizers. Of these, the CYP2D6 ultrarapid metabolism phenotype has been shown to have lower drug levels of both amitriptyline and nortriptyline, so alternative drugs should be considered. The CYP2D6 intermediate and poor metabolism phenotypes have been shown to be associated with an increased risk of side effects and toxicity of both amitriptyline and nortriptyline, meaning a lower starting dose or an alternative drug should be considered. The CYP2C19 poor metabolizer phenotype has also been shown to increase the risk of side effects and toxicity of amitriptyline (but not nortriptyline) due to higher drug levels meaning an alternative drug should be considered.

Photo reference: Clin Pharmacol Ther. 2017 Jul;102(1):37-44. doi: 10.1002/cpt.597. Epub 2017 Feb 13. PMID: 27997040; PMCID: PMC5478479.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) is a group who evaluates the evidence for the use of pharmacogenetics and then develops clinical practice guidelines. For amitriptyline and nortriptyline, extensive guideline information can be found at https://cpicpgx.org/guidelines/guideline-for-tricyclic-antidepressants-and-cyp2d6-and-cyp2c19/ a reference maintained by CPIC.

Here are two videos that review the CPIC guideline for these drugs:
Amitriptyline: https://www.youtube.com/watch?v=euaUk7d-aBg
Nortriptyline: https://www.youtube.com/watch?v=AWYeheV_7_s

 

At UCHealth the use of pharmacogenetics when prescribing amitriptyline or nortriptyline will occur in patients who meet the following conditions:
1) Provided a blood or saliva sample to the CCPM biobank, consented for the return of their results, and this sample has undergone genotyping OR the patient is being seen in a clinic which is currently using pharmacogenetic testing as part of standard care (e.g., the UCHealth GI Oncology Clinic).  
2) Are prescribed amitriptyline or nortriptyline.

For patients enrolled in the biobank, this process takes a minimum of 4-6 weeks but may take several years. Therefore, results will not be available at initial presentation if a patient has not previously enrolled in the biobank.

If you are a provider AND your patient is a CYP2D6 ultrarapid, intermediate, or poor metabolizer, an inline medication warning will appear if you attempt to prescribe or refill either amitriptyline or nortriptyline in UCHealth's EHR. If you are a provider AND your patient is a CYP2D6 normal and a CYP2C19 poor metabolizer, an inline medication warning will appear if you attempt to prescribe or refill amitriptyline (but not nortriptyline) in UCHealth's EHR. If the inline medication warning is visible, links to resources will be listed for your reference. There is patient education text available for UCHealth providers to use in discharge paperwork or the after visit summary (AVS).

 

Visit our Provider FAQs page here.  For immediate questions, secure chat Groups: Pharmacogenomics Service in UCHealth's EHR.