Acute Porphyria Drugs

Acute Porphyria Drug Database

M01AB01 - Indometacin
Propably not porphyrinogenic
PNP
Rationale
Indometacin is metabolized via O-demethylation and N-deacylation. Indometacin is not an inducer or an inhibitor of CYP enzymes 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
Chlorobenzoyl chloromethoxy metylindol acetic acid M=359. Practically insoluble in water.
Therapeutic characteristics
Indometacin is indicated for the treatment of rheumatoid arthritis, arthrosis, MB Bechterew, and other supportive tissue inflammatory conditions. The inhibitory effect of cyclooxygenase-2 activity may counteract prostaglandin-caused prolongation of luteal progesterone production. 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 dyspepsia, nausea, vomiting, abdominal pain and diarrhoea.
Hepatic exposure
Probably significant.
Metabolism and pharmakokinetics
Indometacin is metabolised via O-demethylation and N-deacylation. The first seems not to be dependent on CYP enzymes. In vitro data indicates that CYP2C9 is involved in the O-demethylation (Nakajima 1998 and Zhou 2009), with minor contribution by CYP1A2, CYP2C19 and CYP2D6 (Zhou 2009). The half-life elimination is 2-11 hours. In vitro data indicates that it has low potential to be a clinical inducer of hPXR (Sinz 2006). No drug-drug interactions with indomethacin as a perpetrator are observed (DRUID and Interaktionsdatabasen), which may indicate that indometacin is not an inhibitor or inducer of CYP enzymes.
Personal communication
C. Andersson; patient reports: tolerated (n=1).
Published experience
Indomethacin is listed as safe for use in acute porphyria (Disler 1982, Kalman 1998, Moore 1997 and Palmieri 2004).
IPNet drug reports
Uneventful use reported in 8 patients with acute porphyria.

References

  1. Scientific articles
  2. Disler PB, Blekkenhorst GH, et al. Guidelines for drug prescription in patients with the acute porphyrias. S Afr Med J. 1982 May 1;61(18):656-60. PMID 6123155. #4518
  3. Kalman DR and Bonkovsky HL. Management of acute attacks in the porphyrias. Clin Dermatol. 1998 Mar-Apr;16(2):299-306. #1738
  4. 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
  5. Nakajima M, Inoue T, et al. Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. Drug Metab Dispos. 1998 Mar;26(3):261-6. PMID 9492390. #4620
  6. Palmieri C, Vigushin DM, et al. Managing malignant disease in patients with porphyria. QJM. 2004 Mar;97(3):115-26. #2363
  7. 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
  8. Zhou SF, Zhou ZW, et al. Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. PMID 19515014. #4527
  9. Drug interaction databases
  10. DRUID. Indometacin #2360
  11. Interaktionsdatabasen. Indometacin #2361
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