Acute Porphyria Drugs

Acute Porphyria Drug Database

N06AA10 - Nortriptyline
Propably not porphyrinogenic
PNP
Rationale
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.
Chemical description
Nortriptyline is a metabolite of amitriptyline (ATC code: N06A A09).
Therapeutic characteristics
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.
Metabolism and pharmakokinetics
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.
Published experience
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.

References

  1. Scientific articles
  2. Moore AW 3rd, Coke JM. Acute porphyric disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000 Sep;90(3):257-62. PMID 10982942. #4500
  3. Brøsen K, Kragh-Sørensen P. Concomitant intake of nortriptyline and carbamazepine. Ther Drug Monit. 1993 Jun;15(3):258-60. PMID 8333008. #2717
  4. Disler PB, Blekkenhorst GH, et al. Guidelines for drug prescription in patients with the acute porphyrias. S Afr Med J. 1982 May 1;61(18):656-60. PMID 6123155. #4518
  5. Drewe J. Interaktionen zwischen Antiepileptika und Antidepressiva/Neuroleptika. Epileptologie. 2006. 23:24-28. #2718
  6. Eales L. Porphyria and the dangerous life-threatening drugs. S Afr Med J. 1979 Nov 24;56(22):914-7. PMID 515871. #1250
  7. Fontana E, Dansette PM, Poli SM. Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity. Curr Drug Metab. 2005 Oct;6(5):413-54. PMID 16248836. #2719
  8. Hisaka A, Ohno Y, et al. Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information. Pharmacol Ther. 2010 Feb;125(2):230-48. #1138
  9. Isoherranen N, Hachad H, et al. Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database. Chem Res Toxicol. 2009 Feb;22(2):294-8. #1005
  10. Kalman DR and Bonkovsky HL. Management of acute attacks in the porphyrias. Clin Dermatol. 1998 Mar-Apr;16(2):299-306. #1738
  11. Krummel SJ, Wesner RB. Exacerbation of acute intermittent porphyria by nortriptyline. Drug Intell Clin Pharm. 1986 Jun;20(6):487-9. PMID 3720542. #2722
  12. Mo SL, Zhou ZW, et al. New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. Curr Drug Metab. 2009 Dec;10(10):1075-126. PMID 20167001. #4685
  13. Moore MR, Hift RJ. Drugs in the acute porphyrias--toxicogenetic diseases. Cell Mol Biol (Noisy-le-grand). 1997 Feb;43(1):89-94. PMID 9074793. #1110
  14. Pond SM, Graham GG, et al. Effects of tricyclic antidepressants on drug metabolism. Clin Pharmacol Ther. 1975 Aug;18(2):191-9. #2715
  15. Sarlis NJ, Gourgiotis L. Hormonal effects on drug metabolism through the CYP system: perspectives on their potential significance in the era of pharmacogenomics. Curr Drug Targets Immune Endocr Metabol Disord. 2005 Dec;5(4):439-48. PMID 16375696. #2727
  16. Sinz M, Kim S, et al. Evaluation of 170 xenobiotics as transactivators of human pregnane X receptor (hPXR) and correlation to known CYP3A4 drug interactions. Curr Drug Metab. 2006 May;7(4):375-88. PMID 16724927. #4323
  17. Zhou SF, Xue CC, et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007 Dec;29(6):687-710. PMID 18043468. #4349
  18. Zhou SF, Zhou ZW, et al. Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. PMID 19515014. #4527
  19. Drug interaction databases
  20. Interaksjoner. nortriptylin #2720
  21. Interaktionsdatabasen. nortriptylin #2721
  22. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). #1213
  23. Summary of Product Characteristics
  24. Norwegian medicines agency. Summary of Product Characteristics (SPC). nortriptyline. #2726
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