Amitriptylin does not inhibit or induce CYP2C9. It is not listed as an inhibitor or inducer of any major CYP enzymes in vivo. Risk for gastrointestinal adverse events in the form of obstipation and nausea motivates vigilance against insufficient intake of food, especially of carbohydrate. Amitriptylin is metabolised to nortriptylin, which is classified as Probably not porphyrinogenic (PNP). For more information please refer to the monograph of nortriptylin (ATC code: N06A A10).

Amitriptyline is indicated for the treatment of depression and chronic pain. Very common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are obstipation and nausea. Another very common side effect is tachycardia. A common side effect is fatigue.

Amitriptyline is metabolised by CYP2D6 (Hisaka 2010 and SPC) to nortriptyline, E-10-hydroxyamitriptyline and E-10-hydroxynortriptyline (Zhou 2009). CYP3A4 (Gharahmani 1997 and Zhou 2009), CYP2C9, CYP1A2 (Flockhart 2007 and Zhou 2009) and CYP2C19 (Pelkonen 2008 and Zhou 2009) are listed in addition to CYP2D6, to contribute to the metabolism of amitriptyline (Zhou 2009). In vivo studies have shown that CYP3A plays a relatively minor role in amitriptyline clearance (Venkatakrishnan 2001). Co-administration of amitriptyline with two CYP2C9 substrates, warfarin and tolbutamide, showed that amitriptyline had no effect on the plasma half-lives of the substrates (Pond 1975). This indicates that amitriptyline does not inhibit or induce CYP2C9. Tricyclic antidepressants, which include amitriptyline, does appear to have minimal potential for mechanism-based inhibition of human liver microsomal CYP enzymes involved in drug metabolism (Polasek 2008). Amitriptyline also demonstrated no response in an hPXR transactivation assay (Sinz 2006). It is listed as a weak inhibitor of CYP2C19 in vivo. It is however, not listed as an inhibitor or inducer of any major CYP enzymes in vivo (Isoherranen 2009). No drug-drug interactions with amitriptyline as a perpetrator regarding CYP enzymes are observed (Interaksjoner and Interaktionsdatabasen), which indicate that amitriptyline is not an inhibitor or inducer of CYP enzymes in vivo.

Thunell, patient inquiry: tolerated. (n=1)

There are conflicting experiences on whether amitriptyline is safe or not. Amitriptyline is listed as unsafe for patients with acute porphyria (Moore 1997, 2000). Amitriptyline is listed as safe for patients with acute porphyria (Eales 1979).

Uneventful use reported in 12 patients with acute porphyria. One report of the worsening of an attack leading to hospitalisation of a previously undiagnosed female AIP patient, but the patient was also exposed to other probably porphyrinogenic drugs and other factors that could have contributed to the attack.