Acute Porphyria Drugs

Acute Porphyria Drug Database

N05CD08 - Midazolam
Propably not porphyrinogenic
PNP
Rationale
Midazolam has been shown to be a mechanism-based inhibitor in vitro. However, available data does not indicate that it is an inhibitor or an inducer of CYP enzymes in vivo.
Chemical description
Cyclic tertiary amide functions, such as present in the imidazole grouping, are associated with CYP suicide properties.
Therapeutic characteristics
Midazolam injection is a short-acting sleep-inducing drug which is indicated for conscious sedation, anaesthesia and sedation in intensive care units. Midazolam oromucosal solution is indicated for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to <18 years). Less common side effects are nausea, vomiting and obstipation.
Metabolism and pharmakokinetics
Midazolam is metabolised by CYP3A4 and the main metabolite is alfa-hydroxymidazolam. Alfa-hydroxymidazolam is pharmacologically active, but contributes minimally (about 10%) to the effects of intravenous midazolam (SPC). In healthy volunteers the half-life elimination of midazolam is 1.5-2.5 hours. Midazolam is not listed as an inhibitor or an inducer of CYP3A4 or any other major CYP enzymes in vivo (FDA, Hisaka 2010 and Pelkonen 2008). In vitro this drug has been shown to cause time-dependent inhibition of CYP3A4 (Bomsien 2006 and Podoll 1996), other human CYP450 enzymes (Grimm 2009) and that the 1-hydroxylation of midazolam takes place under destruction of CYP3A (Khan 2002 and Masubuchi 2007). However, no drug-drug interactions with midazolam as a perpetrator have been observed (Interaksjoner and Interaktionsdatabsen), which indicates that midazolam is not an inhibitor or inducer of CYP enzymes in vivo.
Personal communication
Thunell: 3 reports of safe use. Reports of repeated use in children without porphyric side effects.
Published experience
Midazolam is listed as safe in acute porphyria (Gorchein 1997) and has not been associated with human porphyric attacks (Moore 1997). In a review focusing on drugs and the anaesthetic implication in acute porphyrias (James 2000) midazolam is listed in the category Use with caution with the following description: Though safety is not established beyond doubt, the evidence suggests that the drug is unlikely to prove unsafe in practice. It may be used provided no safer alternative is available or suitable. In a case report (Armen 2009) a female AIP patient was given several drugs including midazolam during surgery without triggering an acute attack. The authors conclude that midazolam is safe for use in patients with acute porphyria. The patient was however, also given heme and glucose to inhibit heme synthesis and prevent an acute attack which means that a possible acute attack could have been supressed. In another report midazolam was used uneventfully in a 60 year old, menopausal, AIP patient (Hsieh 2006).
IPNet drug reports
Uneventful use reported in 2 patients with acute porphyria.

References

  1. Scientific articles
  2. Schrag ML and Wienkers LC (2001) Covalent alteration of the CYP3A4 active site: evidence for multiple substrate binding domains. Arch Biochem Biophys 391:49-55. PMID 11414684. #2694
  3. Armen TA, Sai-Sudhakar CB, et al. Anesthetic management for combined double-valve and coronary artery bypass in a patient with acute intermittent porphyria. J Cardiothorac Vasc Anesth. 2009 Jun;23(3):364-8. #2683
  4. Bomsien S, Aderjan R, et al. Effect of psychotropic medication on the in vitro metabolism of buprenorphine in human cDNA-expressed cytochrome P450 enzymes. Epub 2006 Jun 27. #2684
  5. Gorchein A. Drug treatment in acute porphyria. Br J Clin Pharmacol. 1997 Nov;44(5):427-34. PMID 9384458. #1733
  6. 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
  7. 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
  8. Hsieh CH, Hung PC, et al. The use of rocuronium and sevoflurane in acute intermittent porphyria--a case report. Acta Anaesthesiol Taiwan. 2006 Sep;44(3):169-71. PMID 17037005. #4678
  9. James MF, Hift RJ. Porphyrias. Br J Anaesth. 2000 Jul;85(1):143-53. PMID 10928003. #2365
  10. Khan KK, He YQ, Domanski TL, Halpert JR. Midazolam oxidation by cytochrome P450 3A4 and active-site mutants: an evaluation of multiple binding sites and of the metabolic pathway that leads to enzyme inactivation. Mol Pharmacol. 2002 Mar;61(3):495-506. PMID 11854429. #4679
  11. Masubuchi Y, Horie T. Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. Crit Rev Toxicol. 2007 Jun;37(5):389-412. PMID 17612953. #1326
  12. Moore MR, Hift RJ. Drugs in the acute porphyrias--toxicogenetic diseases. Cell Mol Biol (Noisy-le-grand). 1997 Feb;43(1):89-94. PMID 9074793. #1110
  13. 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
  14. Podoll T. D.: Defining the Use of Midazolam as a Probe of CYP3A4 Activity: Sensitive Quantitation of the Metabolites and Characterization of Mechanism-Based Inactivation. University of Washington, Ph.D. Thesis (1996). #3767
  15. Government bodies
  16. U.S Food and Drug Administration (FDA). #1450
  17. Drug interaction databases
  18. Interaksjoner. midazolam #2687
  19. Interaktionsdatabasen. midazolam #2688
  20. Summary of Product Characteristics
  21. Norwegian medicines agency. Summary of Product Characteristics (SPC). Midazolam. #2691
  22. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Buccolam. #2693
  23. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Midazolam injection. #2695
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