Acute Porphyria Drugs

Acute Porphyria Drug Database

N06AB05 - Paroxetine
Propably not porphyrinogenic
PNP
Rationale
Paroxetine is not an inhibitor or an inducer of CYP3A4, CYP2C9 and CYP2C19 in vivo. Risk for gastrointestinal adverse events in the form of loss of appetite, obstipation, diarrhoea and vomiting motivates vigilance against insufficient intake of food, especially of carbohydrate.
Therapeutic characteristics
Paroxetine is indicated for the treatment of major depressive episode, obsessive compulsive disorder, panic disorder with and without agoraphobia, social anxiety disorders/social phobia, generalised anxiety disorder and post-traumatic stress disorder. 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 loss of appetite, obstipation, diarrhoea and vomiting. Other common side effects are dizziness, tremor, headache, somnolence and insomnia. A very common side effect is nausea.
Hepatic exposure
Probably significant
Metabolism and pharmakokinetics
Paroxetine is metabolised by CYP2D6 (Norsk legemiddelhåndbok). Half-life elimination is approximately 24 hours. Paroxetine is listed as a competitive inhibitor of CYP2C9 and CYP2C19 in vitro (Isoherranen 2008). Studies also indicate that it is not a time-dependent inhibitor of CYP3A in vitro (Zimmerlin 2011). Paroxetine caused no changes in the plasma concentration of carbamazepine, valproate or phenytoin (Andersen 1991). Carbamazepine is a substrate of CYP3A4 while valproate and phenytoin are substrates of CYP2C9 and CYP2C19 (Norsk legemiddelhåndbok). Paroxetine did not have any effect on the pharmacokinetics parameters of etravirine, a substrate of CYP3A4, CYP2C9 and CYP2C19, when co-administrated (Kakuda 2011). These data indicate that paroxetine is not an inhibitor or an inducer of CYP3A4, CYP2C9 and CYP2C19 in vivo. Paroxetine is a strong (FDA and Grimm 2009) mechanism-based (Isoherranen 2009) inhibitor of CYP2D6 in vivo (Hisaka 2010, Pelkonen 2008 and SPC). The relative abundance of CYP2D6 in the liver is less than 5 per cent of the total CYP isoforms (Mouly 2009 and Pelkonen 2008). The mechanism-based inhibition of CYP2D6 may lead to increased de novo synthesis of CYP2D6, but with the very low relative abundance of CYP2D6 the potential effect on the total heme biosynthetic flux is expected to be minimal. The use of paroxetine is, therefore, not expected to significantly influence the level of ALA and PGB in patients with an acute porphyria.
Personal communication
C. Andersson: 1 report of safe use.
IPNet drug reports
Uneventful use reported in 11 patients with acute porphyria.

References

  1. Scientific articles
  2. Andersen BB, Mikkelsen M, et al. No influence of the antidepressant paroxetine on carbamazepine, valproate and phenytoin. Epilepsy Res. 1991 Nov-Dec;10(2-3):201-4. #2738
  3. Grimm SW, Einolf HJ, et al. The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America. Drug Metab Dispos. 2009 Jul;37(7):1355-70. PMID 19359406. #4677
  4. 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
  5. 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
  6. Kakuda TN, Schöller-Gyüre M, Hoetelmans RM. Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet. 2011 Jan;50(1):25-39. PMID 21142266. #2741
  7. Mouly S, Meune C, Bergmann JF. Mini-series: I. Basic science. Uncertainty and inaccuracy of predicting CYP-mediated in vivo drug interactions in the ICU from in vitro models: focus on CYP3A4. Intensive Care Med. 2009 Mar;35(3):417-29 PMID 19132343. #2742
  8. 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
  9. Zimmerlin A, Trunzer M, Faller B. CYP3A time-dependent inhibition risk assessment validated with 400 reference drugs. Drug Metab Dispos. 2011 Jun;39(6):1039-46. PMID 21383203. #2748
  10. Drug reference publications
  11. Norsk legemiddelhåndbok. Fenytoin. #2743
  12. Norsk legemiddelhåndbok. Karbamazepin. #2744
  13. Norsk legemiddelhåndbok. Paroksetin. #2745
  14. Norsk legemiddelhåndbok. Valproat. #2746
  15. Government bodies
  16. U.S Food and Drug Administration (FDA). #1450
  17. Summary of Product Characteristics
  18. Norwegian medicines agency. Summary of Product Characteristics (SPC). Paroksetin. #2747
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