Acute Porphyria Drugs

Acute Porphyria Drug Database

N06AB10 - Escitalopram
Propably not porphyrinogenic
PNP
Rationale
Escitalopram is an inhibitor of CYP1A2 in vivo, but is not listed as a mechanism-based inhibitor of CYP1A2 or any other major CYP enzymes. Risk for gastrointestinal adverse events in the form of nausea, diarrhoea, constipation and vomiting motivates vigilance against insufficient intake of food, especially of carbohydrate.
Chemical description
Escitalopram is the S-enantiomer of citalopram and a selective serotonin (5-HT) reuptake inhibitor.
Therapeutic characteristics
Escitalopram is indicated for the treatment of major depressive episodes, panic disorder, social anxiety disorder, generalised anxiety disorder and obsessive-compulsive 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 nausea, diarrhoea, constipation and vomiting. Other common side effects are reduced or increased appetite, insomnia, somnolence, dizziness, paraesthesia, tremor, arthralgia, myalgia, fatigue and pyrexia.
Metabolism and pharmakokinetics
Escitalopram is mainly metabolised by CYP2C19 with minor contribution by CYP3A4 and CYP2D6 (SPC). It is metabolised to S-demethylcitalopram and S-didemthylcitalopram which has no pharmacological activity in vivo (Pastoor 2014). Half-life elimination is approximately 30 hours. In vitro studies have shown that escitalopram and its metabolites are negligible inhibitors of CYP2C19 (SPC), CYP1A2, CYP2C9, and CYP3A4 (Spina 2012). Others have shown that escitalopram does not inhibit CYP3A4, CYP1A2, CYP2C19 and CYP2E1 in vitro (Pastoor 2014). Escitalopram did not significantly affect the pharmacokinetics of ritonavir, a CYP3A4 substrate, when co-administrated (Gutierrez 2003 and Rao 2007). This indicates that escitalopram is not an inhibitor or inducer of CYP3A4 in vivo. Escitalopram increased the AUC of rasagiline (CYP1A2 substrate) by 42% when co-administrated (Hilli 2009 and Spina 2012). This indicates that escitalopram is an inhibitor of CYP1A2 in vivo. It is however, not listed as a mechanism-based inhibitor of CYP1A2, or inhibitor or inducer of any other major CYP enzymes (FDA, Hisaka 2010, Isoherranen 2009 and Pelkonen 2008). Another in vivo study showed that escitalopram increased the serum concentration of apiprazole (CYP3A4 and CYP2D6 substrate) by 20% when co-administrated (Spina 2012). Escitalopram is listed as a weak inhibitor of CYP2D6 in vivo (FDA, Isoherranen 2009 and SPC).
IPNet drug reports
Uneventful use reported in 7 patients with acute porphyria.

References

  1. Scientific articles
  2. Spina E, Trifirò G, Caraci F. Clinically significant drug interactions with newer antidepressants. CNS Drugs. 2012 Jan 1;26(1):39-67. #2764
  3. Gutierrez MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther. 2003 Apr;25(4):1200-10. PMID 12809966. #2761
  4. Hilli J, Korhonen T, Laine K. Lack of clinically significant interactions between concomitantly administered rasagiline and escitalopram. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Nov 13;33(8):1526-32. PMID 19733607. #2732
  5. 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
  6. 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
  7. Pastoor D, Gobburu J. Clinical pharmacology review of escitalopram for the treatment of depression. Expert Opin Drug Metab Toxicol. 2014 Jan;10(1):121-8. PMID 24289655. #2762
  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. Rao N. The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet. 2007;46(4):281-90. PMID 17375980. #2763
  10. Government bodies
  11. U.S Food and Drug Administration (FDA). #1450
  12. Summary of Product Characteristics
  13. Norwegian medicines agency. Summary of Product Characteristics (SPC). Rasagiline. #2632
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