Nortriptyline does not inhibit or induce CYP2C9. It is not listed as an inhibitor or an inducer of any other 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.

Nortriptyline is a metabolite of amitriptyline (ATC code: N06A A09).

Nortriptyline is indicated for the treatment of depressions. 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.

Nortriptyline is metabolised by CYP2D6 (SPC) to desmethyl nortriptyline, E-10-OH-desmethyl nortriptyline E-10-OH-desmethyl nortriptyline and E-10-OH-nortriptyline (Zhou 2009). Nortriptyline is listed as a weak mechanism-based inhibitor of CYP2D6 in vivo (Isoherranen 2009). CYP1A2 (Sarlis 2005), CYP3A4 (Drewe 2006 and Zhou 2007) and CYP2C19 (Drewe 2006) are listed in addition to CYP2D6, to contribute to the metabolism of nortriptyline. In vitro data indicate that CYP2C9 contributes to the metabolism of nortriptyline to a minor degree (Mo 2009). Nortriptyline is listed as an inhibitor of CYP3A4 in vitro (Zhou 2007). It is a mechanism-based inhibitor toward recombinant CYP2C19 and CYP3A4, but not human liver microsomal CYP2C19 and CYP3A4 in vitro (Polasek 2008). Co-administration of nortriptyline with two CYP2C9 substrates, warfarin and tolbutamide, showed that nortriptylin had no effect on the plasma half-lives of the substrates (Pond 1975). This indicates that nortriptyline does not inhibit or induce CYP2C9. Nortriptyline demonstrated no response in an hPXR transactivation assay (Sinz 2006). It is also not listed as an inhibitor or inducer of any major CYP enzymes in vivo (Isoherranen 2009). No drug-drug interactions with nortriptyline as a perpetrator regarding major CYP enzymes are observed (Interaksjoner and Interaktionsdatabasen), which indicate that nortriptyline is not an inhibitor or inducer of any major CYP enzymes in vivo.

Several references list nortryptiline as safe for patients with acute porphyria (Disler 1982, Eales 1979 and Moore 2000). There are however, others who list it as unsafe. Nortriptyline is listed with conflicting experimental evidence of porphyrinogenicity (Hift 1997) and as theoretically risky (Kalman 1998). Nortriptyline has in a report (Krummel 1986) been suspected to have induced an acute attack in a male AIP patient. Three days after the patient had started treatment with nortriptylin; he developed acute right lower quadrant abdominal pain and had one emesis (Krummel 1986). But the occurrence of an acute porphyric attack is questionable since this diagnosis was based on elevated urinary total porphyrins and not on ALA/PBG. If an attack was present, a causal relation between nortriptyline and the event is also dubious since the presence of other provoking factors like insomnia and psychological stress may provide a plausible explanation. This report is therefore not taken into account.