Acute Porphyria Drugs

Acute Porphyria Drug Database

J01XD01 - Metronidazole
Propably not porphyrinogenic
PNP
Rationale
Metronidazole is a substrate and possibly a weak inhibitor of CYP3A4. It is an inhibitor of CYP2C9. There are no data indicating mechanism-based inhibition of CYP3A4 or CYP2C9, and it is not listed as an inducer of CYP enzymes. Side effects such as nausea, vomiting and diarrhoea may be potentially porphyrinogenic through reduction in carbohydrate intake.
Chemical description
Metyl-5- nitroimidazol ethanol. M=171. Slightly soluble in water. Cyclic tertiary amine.
Therapeutic characteristics
Metronidazole is indicated for the treatment of infections caused by Trichomonas vaginalis, Giaria lamblia, Entamoeba histolytica, bacterial vaginosis, and anaerobe infections. It is also indicated for prophylactic use for colon and rectum surgery and for the treatment of active Morbus Crohn. Common side effects that can be confused with an acute porphyria attack are nausea, vomiting, diarrhoea and abdominal pain. Dark colouring of urine may take place.
Metabolism and pharmakokinetics
Metronidazole is a substrate of CYP3A4 (Wang 2000). 30-60% is metabolised mainly in the liver via oxidation and 60-80% is excreted as unchanged drug. The elimination half-life is 6-10 hours. Metronidazole is listed as a weak CYP3A4 inhibitor (Cheng 2010, Obach 2006) and in vitro studies have shown that it is unlikely to be a perpetrator in drug-drug interactions (Polasek 2011, Sinz 2006). There are no data indicating mechanism-based inhibition. A case study showed that ciclosporin, a CYP3A4 substrate, increased in plasma concentration when co-administered with metronidazole (Herzig 1999). Other in vivo data have on the other hand, showed that metronidazole is not an inhibitor of CYP3A4 (Blyden 1988, Wang 2000). It is listed as a weak inhibitor of CYP2C9 (Holsetin 2012, Isoherranen 2009, Mouly 2009). There are conflicting in vivo data on whether metronidazole inhibits CYP2C9 or not when co-administrated with phenytoin. It has been observed that metronidazole increased the area under the curve and the half-life elimination, and decreased the clearance of phenytoin (Blyden 1988), but another study showed that metronidazole did not affect the pharmacokinetics of phenytoin (Jensen 1985). Other in vivo data have shown that there was a statistically significant increase in INR (Laine 2000) and in drug plasma concentration in patients, when warfarin was co-administered with metronidazole (O’Reilly 1976). Warfarin is a substrate of CYP2C9 and these data indicates that metronidazole can inhibit CYP2C9. There are however, no data indicating mechanism-based inhibition.
Personal communication
Thunell: 2 patient reports of tolerance.
IPNet drug reports
Systemic use: uneventful use reported in 6 patients with acute porphyria (1 report for suppository, G01A F01. 5 reports for infusion, J01X D01). Topical use: uneventful use reported in 3 patients with acute porphyria (cream, D06B X01).

References

  1. Scientific articles
  2. Blyden GT, Scavone JM, Greenblatt DJ. Metronidazole impairs clearance of phenytoin but not of alprazolam or lorazepam. J Clin Pharmacol. 1988 Mar;28(3):240-5. PMID 3360972. #1002
  3. Cheng JW, Frishman WH, Aronow WS. Updates on cytochrome p450-mediated cardiovascular drug interactions. Dis Mon. 2010 Mar;56(3):163-79. PMID 20189501. #1003
  4. Holstein A, Beil W, Kovacs P. CYP2C metabolism of oral antidiabetic drugs--impact on pharmacokinetics, drug interactions and pharmacogenetic aspects. Expert Opin Drug Metab Toxicol. 2012 Dec;8(12):1549-63. PMID 23153186. #1004
  5. 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
  6. Jensen JC, Gugler R. Interaction between metronidazole and drugs eliminated by oxidative metabolism. Clin Pharmacol Ther. 1985 Apr;37(4):407-10. PMID 3979002. #1006
  7. Laine K, Forsström J, et al. Frequency and clinical outcome of potentially harmful drug metabolic interactions in patients hospitalized on internal and pulmonary medicine wards: focus on warfarin and cisapride. Ther Drug Monit. 2000 Oct;22(5):503-9. PMID 11034253. #4320
  8. Mouly S, Meune C, Bergmann JF. Mini-series: I. Basic science. Uncertainty and inaccuracy of predicting CYP-mediated in vivo drug interactions in the ICU from in vitro models: focus on CYP3A4. Intensive Care Med. 2009 Mar;35(3):417-29. PMID 19132343. #1008
  9. OReilly RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med. 1976 Aug 12;295(7):354-7. PMID 934223. #4321
  10. 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
  11. Sinz M, Kim S, et al. Evaluation of 170 xenobiotics as transactivators of human pregnane X receptor (hPXR) and correlation to known CYP3A4 drug interactions. Curr Drug Metab. 2006 May;7(4):375-88. PMID 16724927. #4323
  12. Wang JS, Backman JT, et al. Effects of metronidazole on midazolam metabolism in vitro and in vivo. Eur J Clin Pharmacol. 2000 Nov;56(8):555-9. PMID 11151744. #4324
  13. Drug reference publications
  14. Up to date. Metronidazole. #1014
  15. Summary of Product Characteristics
  16. Norwegian medicines agency. Summary of Product Characteristics (SPC). Metronidazol. #1654
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