Acute Porphyria Drugs

Acute Porphyria Drug Database

A02BC03 - Lansoprazole
Propably not porphyrinogenic
PNP
Rationale
Lansoprazole is metabolized by CYP2C19 and CYP3A4. It is not listed as a mechanism-based inhibitor of CYP enzymes and is not an inducer of CYP1A2 or CYP3A4. 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
Pyridylsulphinyl benzamidazole derivative with secondary as well as tertiary amine functions.
Therapeutic characteristics
Lansoprazole is indicated for the treatment of duodenal and gastric ulcer, gastroesophageal reflux disease, esophagitis, Helicobacter pylori eradication, ventricular hyper secretion and NSAID-associated gastric ulcer. Common side effects of lansoprazole that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are diarrhoea, nausea and vomiting. Other common side effects are obstipation and abdominal pain.
Metabolism and pharmakokinetics
Lansoprazole is metabolized primarily by CYP2C19 with minor contribution by CYP3A4 (Naritomi 2003 and SPC). In vitro studies have shown that lansoprazole is a weak inhibitor of CYP3A4, 2B6, 2D6, 2C9, 2C8 and 1A2 (Zyvaga 2012). The elimination half-life is 1-2 hours. Co-administration of lansoprazole with tacrolimus, a CYP3A4 substrate and P-gp substrate, increased the AUC of tacrolimus up to 81 % (Itagaki 2004 and SPC). These data may indicate that lansoprazole is an inhibitor of CYP3A4. In vitro data indicates that lansoprazole does not have the potential to be a mechanism-based inhibitor (Zyvaga 2012). Other studies state that it is a competitive inhibitor of CYP2C19 and CYP2C9, a non-competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6 (Ishizaki 1999, Ko 1997 and Li 2004). Lansoprazole is listed as an inducer of CYP3A4 in vitro (Rendic 2002) and in vitro studies have also shown that it can induce CYP1A1 and CYP1A2 (Curi-Pedrosa 1994, Rendic 2002 and Krusekopf 2003). Data from clinical studies indicates that lansoprazole does not induce CYP1A2 activity (Andersson 1998 and Dilger 1999). When lansoprazole was co-administrated with ivabradine, a CYP3A4 substrate, no statistically significant effect was seen on the AUC of ivabradine (Portolés 2006). This may indicate that lansoprazole does not inhibit or induce CYP3A4.
IPNet drug reports
Uneventful use reported in 9 patients with acute porphyria.

References

  1. Scientific articles
  2. Andersson T, Holmberg J, et al. Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. Br J Clin Pharmacol. 1998 Apr;45(4):369-75. PMID 9578184. #4332
  3. Curi-Pedrosa R, Daujat M, et al. Omeprazole and lansoprazole are mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture. J Pharmacol Exp Ther. 1994 Apr;269(1):384-92. PMID 8169844. #4333
  4. Dilger K, Zheng Z, et al. Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline. Br J Clin Pharmacol. 1999 Sep;48(3):438-44. #1030
  5. Itagaki F, Homma M, et al. Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations. J Pharm Pharmacol. 2004 Aug;56(8):1055-9. PMID 15285851. #4334
  6. Ko JW, Sukhova N et al. Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispos. 1997 Jul;25(7):853-62. #1032
  7. 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
  8. 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
  9. Maguire M, Franz T, Hains DS. A clinically significant interaction between tacrolimus and multiple proton pump inhibitors in a kidney transplant recipient. Pediatr Transplant. 2012 Sep;16(6):E217-20. #1035
  10. Naritomi Y, Terashita S, Kagayama A. Identification and relative contributions of human cytochrome P450 isoforms involved in the metabolism of glibenclamide and lansoprazole: evaluation of an approach based on the in vitro substrate disappearance rate. Xenobiotica. 2004 May;34(5):415-27. #1036
  11. Portolés A, Calvo A, et al. Lack of pharmacokinetic interaction between omeprazole or lansoprazole and ivabradine in healthy volunteers: an open-label, randomized, crossover, pharmacokinetic interaction clinical trial. J Clin Pharmacol. 2006 Oct;46(10):1195-203. PMID 16988209. #1038
  12. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. PMID 11996015. #1039
  13. 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
  14. 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
  15. Summary of Product Characteristics
  16. Norwegian medicines agency. Summary of Product Characteristics (SPC). lansoprazol. #1037
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