Acute Porphyria Drugs

Acute Porphyria Drug Database

R03DC03 - Montelukast
Possibly porphyrinogenic
PSP
Important Information
A very common side effect of montelukast is upper respiratory tract infection. Since infections have a potential to trigger acute porphyric attacks vigilance is motivated regarding signs or symptoms of infection and/or possible symptoms of a porphyric attack.
Side effects
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 vomiting, nausea, diarrhoea and pyrexia.
Rationale
Montelukast is listed as a moderate inducer of CYP1A2 in vivo. CYP1A2 amounts quantitatively to more than 10 % of the CYPs in the liver. A moderate induction of this CYP isoenzyme may possibly increase the activity of ALAS-1 to a level which is sufficient to precipitate an attack.
Chemical description
Leukotriene receptor antagonist containing functional groups like chloroquinoline, cyclopropan, aliphatic sulfide and acetic acid.
Therapeutic characteristics
Montelukast is indicated for the treatment of asthma. It is administered orally.
Metabolism and pharmacokinetics
Montelukast is metabolised mainly by CYP2C8, with contributions by CYP3A4 and CYP2C9 to a minor degree (Karonen 2012). In vitro data indicates that therapeutic plasma concentrations of montelukast do not inhibit CYP3A4, CYP2C9, CYP1A2, CYP2A6, CYP2C19 and CYP2D6 (SPC). In vitro studies in human liver microsomes found montelukast to be a selective competitive inhibitor of CYP2C8, but not to be a mechanism-based inhibitor (Walsky 2005). Despite being a CYP2C8 inhibitor in vitro, clinical drug-drug interaction studies with pioglizazone and rosiglitazone, CYP2C8 substrates, showed that montelukast does not inhibit CYP2C8 in vivo (Jaakkola 2006, Kim 2007). The concentrations of ethinyl estradiol and norethinedrone (substrates of CYP3A4) were unaffected when co-administrated with montelukast for 8 days (Jarvis 2000). This might indicate that montelukast is not an inhibitor or an inducer of CYP3A4, but it was not specified which pharmacokinetic parameters that were measured in the study. Montelukast demonstrated activity in an hPXR transactivation assay, but the clinical induction is predicted to be low (Sinz 2006). It is not known to inactivate any enzymes via mechanism-based inhibition in vitro (Obach 2007). Montelukast is listed as a moderate inducer of CYP1A2 in vivo (FDA). However, in a clinical dose (10 mg) study montelukast decreased the pharmacokinetics of theophylline (substrate of CYP1A2 and to a minor degree, CYP3A4) by 8% (Jarvis and Markham 2000), which indicates that montelukast is a weak inducer. Studies have shown that when co-administrated, montelukast do not have any significant effect on the AUC of warfarin (a CYP2C9 substrate) (Jarvis and Markham 2000 and Van Hecken 1999), which indicates that montelukast is not an inhibitor or an inducer of CYP2C9.
IPNet drug reports
Uneventful use reported in 1 patient with acute porphyria.

References

  1. Scientific articles
  2. Jarvis, B. and A. Markham (2000). "Montelukast: a review of its therapeutic potential in persistent asthma." Drugs 59(4): 891-928. #2885
  3. Kim, K. A., P. W. Park, et al. (2007). "Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans." Br J Clin Pharmacol 63(3): 339-345. #2887
  4. Obach, R. S., R. L. Walsky, et al. (2007). "Mechanism-based inactivation of human cytochrome p450 enzymes and the prediction of drug-drug interactions." Drug Metab Dispos 35(2): 246-255. #2889
  5. Polasek, T. M., F. P. Lin, et al. (2011). "Perpetrators of pharmacokinetic drug-drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment." Br J Clin Pharmacol 71(5): 727-736. #1789
  6. Sinz, M., S. Kim, et al. (2006). "Evaluation of 170 xenobiotics as transactivators of human pregnane x receptor (hPXR) and correlation to known CYP 3A4 interactions." Curr Drug Met 7: 375-388. #2890
  7. Van Hecken, A., M. Depre, et al. (1999). "Effect of montelukast on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers." J Clin Pharmacol 39(5): 495-500. #2893
  8. Jaakkola T, Backman JT, et al. Montelukast and zafirlukast do not affect the pharmacokinetics of the CYP2C8 substrate pioglitazone. Eur J Clin Pharmacol. 2006 Jul;62(7):503-9. #2884
  9. Karonen T, Neuvonen PJ, et al. CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast. Br J Clin Pharmacol. 2012 Feb;73(2):257-67. #2886
  10. Walsky RL, Obach RS, et al. Selective inhibition of human cytochrome P4502C8 by montelukast. Drug Metab Dispos. 2005 Mar;33(3):413-8. PMID 15608135. #4715
  11. Drug interaction databases
  12. U.S. Food and Drug Administration (FDA). (16.09.2011). "Drug Developement and Drug Interactions: Table of Substrates, Inhibitors and Inducers." Retrieved 04.07.2013, from #2892
  13. Summary of Product Characteristics
  14. Norwegian medicines agency. Summary of Product Characteristics (SPC). Montelukast. #2888
  15. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Montelukast. #2891
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