Acute Porphyria Drugs

Acute Porphyria Drug Database

N06AA09 - Amitriptyline
Propably not porphyrinogenic
PNP
Rationale
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).
Therapeutic characteristics
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.
Metabolism and pharmakokinetics
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.
Personal communication
Thunell, patient inquiry: tolerated. (n=1)
Published experience
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).
IPNet drug reports
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.

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. 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
  4. Eales L. Porphyria and the dangerous life-threatening drugs. S Afr Med J. 1979 Nov 24;56(22):914-7. PMID 515871. #1250
  5. Ghahramani P, Ellis SW,et al. Cytochromes P450 mediating the N-demethylation of amitriptyline. Br J Clin Pharmacol. 1997 Feb;43(2):137-44. #2711
  6. 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
  7. 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
  8. 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
  9. Pelkonen O, Turpeinen M, et al. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008 Oct;82(10):667-715. PMID 18618097. #4347
  10. Polasek TM, Miners JO. Time-dependent inhibition of human drug metabolizing cytochromes P450 by tricyclic antidepressants. Br J Clin Pharmacol. 2008 Jan;65(1):87-97. PMID 17662092. #2709
  11. Pond SM, Graham GG, et al. Effects of tricyclic antidepressants on drug metabolism. Clin Pharmacol Ther. 1975 Aug;18(2):191-9. #2715
  12. 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
  13. Venkatakrishnan K, Schmider J, et al. Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies. J Clin Pharmacol. 2001 Oct;41(10):1043-54. PMID 11583471. #4684
  14. 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
  15. Drug interaction databases
  16. Interaksjoner. amitriptylin #2712
  17. Interaktionsdatabasen. amitriptylin #2713
  18. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). #1213
  19. Summary of Product Characteristics
  20. Norwegian medicines agency. Summary of Product Characteristics (SPC). Amitriptyline. #2714
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