Acute Porphyria Drugs

Acute Porphyria Drug Database

M01AB05 - Diclofenac
Propably not porphyrinogenic
PNP
Rationale
Diclofenac is listed as a mechanism-based inhibitor of CYP2C9 in vitro but shows no inhibition in vivo. It is also listed as a mechanism-based inhibitor of CYP3A4 in vitro. The potential inactivation of CYP3A4 is, however, not regarded clinical important since concentrations necessary for significant inactivation are much higher than clinical blood concentrations of this drug. Several references reports acute attacks following the use of diclofenac, but the reports are of low quality and limited or lacking data makes it very problematic to evaluate the causality between diclofenac and the attacks. Uneventful uses are reported in 41 patients with acute porphyria. Risk for gastrointestinal adverse events in the form of nausea and diarrhoea motivates vigilance against insufficient intake of food, especially of carbohydrate.
Therapeutic characteristics
Diclofenac is indicated for relief of pain and inflammation. 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, nausea, dyspepsia and anorexia. Other common side effects are epigastric and abdominal pain, headache and dizziness.
Metabolism and pharmacokinetics
Diclofenac is a substrate of CYP2C9 (Pelkonen 2008). The half-life elimination is 1-2 hours. In vitro studies in human liver preparations indicate that both CYP2C9 and CYP3A4 are involved in the metabolism of diclofenac (Tang 1999). Diclofenac is listed as a weak mechanism-based inhibitor in vivo (Isoherranen 2009), but data supporting this could however, not be found. In a crossover study co-administration of tolbutamide, a CYP2C9 substrate (Miners 1996), with diclofenac and placebo showed that the plasma tolbutamide levels were almost identical between the two treatments (Fowler 1979). This indicates that diclofenac does not inhibit CYP2C9 in vivo. Diclofenac has also been found to be a mechanism-based inhibitor of CYP3A4 in vitro (Masubuchi 2002). Diclofenac can inactivate CYP3A4 at a rate (kinact) of 0.246 min−1 and a KI of 1.64 mM (Masubuchi 2002). This inactivation may not be important in the clinical setting since the diclofenac concentrations necessary for significant inactivation (> 1 mM) are much higher than clinical blood concentrations of this drug (low µM range) (Johnson 2008).
Published experience
Three reports of attacks in AIP patients following the use of diclofenac: - Kumar 2010. This report is of low quality with very limited data which makes it problematic to evaluate the causality. - Yamamori 1999. The patient did not experience any symptoms of an attack. She had elevation of ALA and the excretion of porphyrin derivatives rose, but it is not unusual for these values to fluctuate during an inflammation (she had hepatitis and gastroenteritis) because of increased heme synthesis. Therefore the report did not confirm that diclofenac precipitated an acute attack of porphyria. - Zoanetti 2011. The patient was given tinidazole which have side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack. These side effects are abdominal pain, anorexia, diarrhoea, nausea and vomiting, some of them which she also experienced and recognised as symptoms of acute porphyria. Her attack was also not documented because of lacking data of urinary ALA/PGB. Use with extreme caution only (James 2000).
IPNet drug reports
Uneventful use reported in 41 patients with acute porphyria. One report of worsening of a beginning acute porphyric attack in a female with AIP. The attack required hospitalisation and lead to serious irreversible neurological damage. Causality is possible, but is less likely because of other factors that could have induced and worsened the attack.

References

  1. Scientific articles
  2. Zoanetti, G., Metz, M. “AIP; It’s the real thing!” Porphyrins and Porphyrias 2011, Cardiff, Wales, April 10-14th 2011. #2369
  3. Fowler PD. Diclofenac sodium (Voltarol): drug interactions and special studies. Rheumatol Rehabil. 1979;Suppl 2:60-8. PMID 394276. #2364
  4. 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
  5. James MF, Hift RJ. Porphyrias. Br J Anaesth. 2000 Jul;85(1):143-53. PMID 10928003. #2365
  6. Johnson WW. Cytochrome P450 inactivation by pharmaceuticals and phytochemicals: therapeutic relevance. Drug Metab Rev. 2008;40(1):101-47. PMID 18259986. #1720
  7. 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
  8. Masubuchi Y, Ose A, Horie T. Diclofenac-induced inactivation of CYP3A4 and its stimulation by quinidine. Drug Metab Dispos. 2002 Oct;30(10):1143-8. PMID 12228192. #2367
  9. Miners JO, Birkett DJ. Use of tolbutamide as a substrate probe for human hepatic cytochrome P450 2C9. Methods Enzymol. 1996;272:139-45. PMID 8791771. #2366
  10. 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
  11. Yamamori I, Asai M, et al. Prevention of premenstrual exacerbation of hereditary coproporphyria by gonadotropin-releasing hormone analogue. Intern Med. 1999 Apr;38(4):365-8. PMID 10361911. #4621
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