Amitriptyline
Amitriptyline is used in relieving symptoms of depression, especially endogenous depression, that is more likely to respond to the treatment than other depressive states. Drugs that inhibit or induce the metabolic reaction of CYP450 enzymes can affect the metabolism of amitriptyline hence increasing the risk of adverse effects or changes in efficacy (English, Dortch, Ereshefsky, & Jhee, 2015). Several hepatic isoenzymes exhibit single nucleotide polymorphisms (SNPs) that can impact the enzyme’s expression or its metabolic capacities. It produces variable phenotypes in CYP450 activity, including rapid metabolism of debrisoquine by ultra-rapid metabolizers of CYPD26 or increased isoniazid toxicity in slow acetylators of N-acetyl transferase.
Dean (2017) indicates that CYP2C19 and CYP2D6 pathways mainly metabolize amitriptyline. Its metabolism by CYP2C19leads to active metabolites that include nortriptyline that is also a tricyclic antidepressant. Metabolism of amitriptyline that is catalyzed by CYP2D6 leads to the formation of a less active 10-hydroxy metabolite. CYP2D6 ultra-rapid metabolizers” metabolizer individuals have more than two normal function alleles while CYP2C19 ultra rapid metabolizers” carry two increased function alleles. Individuals who re poor metabolizers of both CYP2C19 and CYP2D6 carry two no function alleles for CYP2C19 and CYP2D6.
Amitriptyline is a highly lipophilic molecule. It is readily absorbed from the gastrointestinal tract and extensively metabolized on the first pass through the liver. Most of it is excreted from the body through the urine as free metabolites or glucuronide or sulfate conjugates within 24 hours (Davis, 2020). About two percent of the unchanged drug is excreted through the urine. There are small amounts that are excreted in feces. It has an elimination half-life of twenty-five hours, while its distribution is 10 to 50l/kg.
Reference
Davis, M. P. (2020). Amitriptyline and Depressions. Neuro-Psychopharmacotherapy, 1-19.
Dean, L. (2017). Amitriptyline therapy and CYP2D6 and CYP2C19 genotype.
English, B. A., Dortch, M., Ereshefsky, L., & Jhee, S. (2015). Clinically significant psychotropic drug-drug interactions in the primary care setting. Current psychiatry reports, 14(4), 376-390.