Acute Porphyria Drugs

Acute Porphyria Drug Database

A02BC04 - Rabeprazole
Propably not porphyrinogenic
PNP
Rationale
Rabeprazole is mainly metabolized non-enzymatically with minor contributions by CYP2C19 and CYP3A4. Clinical data indicates that rabeprazole is a weak inhibitor of CYP2C19, but no data indicates mechanism-based inhibition. It is not an inhibitor or inducer of CYP1A2 in vivo. Risk for gastrointestinal adverse events in the form of nausea, vomiting and diarrhoea motivates vigilance against insufficient intake of food, especially of carbohydrate.
Chemical description
Pyridylbenzamidazole derivative, with secondary as well as tertiary amine functions.
Therapeutic characteristics
Rabeprazole is a proton pump inhibitor used in the treatment of active duodenal ulcer, active benign gastric ulcer, symptomatic erosive or ulcerative gastro-oesophageal reflux disease, gastro-oesophageal reflux disease long-term management, symptomatic treatment of moderate to very severe gastro-oesophageal reflux disease, Zollinger-Ellison syndrome, therapeutic or preventive in NSAID-treatment and in combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori in patients with peptic ulcer disease. 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 diarrhoea, vomiting and nausea. Other common side effects are abdominal pain, constipation, back pain, non-specific musculoskeletal pain, asthenia, influenza like illness, flatulence, cough, pharyngitis, rhinitis, headache, dizziness and infections.
Hepatic exposure
Probably not significant
Metabolism and pharmakokinetics
The metabolism of rabeprazole is mainly and almost complete non-enzymatic (Horn 2004 and Shi 2008), with minor contribution by CYP2C19 and CYP3A4 (Ishizaki 1999, Itagaki 2004 and Shi 2008). In vitro data indicates that it is then stereoselectively re-oxidized by CYP3A4 mainly to (R)-rabeprazole (Miura 2006). In vitro studies have shown that rabeprazole is a weak inhibitor of CYP3A4, 2B6, 2D6, 2C9, 2C8 and 1A2. (Zhou 2007 and Zyvaga 2012). In vitro studies indicates that it is a competitive inhibitor of CYP3A4, CYP2C19 (Ishizaki 1999) and CYP2C9 (Li 2004). A clinical study showed that rabeprazole increased the AUC of lansoprazole, a CYP2C19 substrate, by 15% (Itagaki 2004) which indicates that it is a weak inhibitor of CYP2C19. In vitro data indicates that rabeprazole has low potential to induce hPXR (Sinz 2006). Rabeprazole has been shown in vitro to induce CYP1A1 and CYP1A2 (Krusekopf 2003) and at expected human plasma concentrations it does not induce or inhibit CYP3A4 (SPC). Rabeprazole does not interact with theophylline, a CYP1A2 substrate, which indicates that it does not inhibit or induce CYP1A2 in vivo (Stedman 2000). Rabeprazole has low potential for drug interactions involving CYP enzymes (Horn 2004 and Shi 2008) and is also listed as an unlikely major perpetrator of CYP2C19 (Polsaek 2011).
Published experience
Two reports of attacks of acute porphyria in AIP patients following the use of rabeprazole (Kumar, 2010). The reports are however, of low quality with very limited data which makes it problematic to evaluate the causality.
IPNet drug reports
Uneventful use reported in 3 patients with acute porphyria.

References

  1. Scientific articles
  2. Horn J. Review article: relationship between the metabolism and efficacy of proton pump inhibitors--focus on rabeprazole. Aliment Pharmacol Ther. 2004 Nov;20 Suppl 6:11-9. #1042
  3. Ishizaki T, Horai Y. Review article: cytochrome P450 and the metabolism of proton pump inhibitors emphasis on rabeprazole. Aliment Pharmacol Ther. 1999 Aug;13(3):27-36. #3411
  4. Krusekopf S, Roots I, et al. Time-dependent transcriptional induction of CYP1A1, CYP1A2 and CYP1B1 mRNAs by H+/K+ -ATPase inhibitors and other xenobiotics. Xenobiotica. 2003 Feb;33(2):107-18. PMID 12623754. #4335
  5. Kumar S, Sharma Net al. Spectrum of emergency department presentation in patients of acute intermittent porphyria: Experience from a North Indian tertiary care center. Neurol India [serial online] 2010 [cited 2010 Jun 30];58:95-8. PMID 20228472. #4336
  6. Li XQ, Andersson TB et al. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome p450 activites. Drug Metab Dispos. 2004 Aug;32(8):821-7. #1034
  7. Miura M, Satoh S, et al. Stereoselective metabolism of rabeprazole-thioether to rabeprazole by human liver microsomes. Eur J Clin Pharmacol. 2006 Feb;62(2):113-7. PMID 16389533. #4337
  8. Polasek TM, Lin FP, et al. Perpetrators of pharmacokinetic drug-drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment. Br J Clin Pharmacol. 2011 May;71(5):727-36. PMID 21223357. #4322
  9. Shi S, Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol. 2008 Oct;64(10):935-51 PMID 18679668. #1047
  10. Sinz et al. Evaluation of 170 xenobiotics as transactivators of human Pregnane X receptor (PXR) and correlation to known Cyp3A4 interactions. Current drug metabolism 2006; 7:375-88. #1040
  11. Stedman CA, Barclay ML. Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther. 2000 Aug;14(8):963-78. PMID 10930890. #1048
  12. 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. #4338
  13. Zvyaga T, Chang SY et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos. 2012 Sep;40(9):1698-711. PMID 22648560. #1041
  14. Summary of Product Characteristics
  15. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). (rabeprazole) #1049
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