Acute Porphyria Drugs

Acute Porphyria Drug Database

M04AB01 - Probenecid
Propably not porphyrinogenic
PNP
Rationale
Probenecid is an inhibitor of CYP2C9 and CYP1A2, but is not listed as a mechanism-based inhibitor. No induction of any major CYP enzymes has been described. Risk for gastrointestinal adverse events in the form of nausea motivates vigilance against insufficient intake of food, especially of carbohydrate.
Chemical description
Di-propyl sulphonamoyl benzoic acid. M= 285. Practically insoluble in water.
Therapeutic characteristics
Probenecid is indicated for the treatment of arthritis urica. Common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack is nausea.
Metabolism and pharmakokinetics
Probenecid is extensively metabolised by glucuronide conjugation and by oxidation of the alkyl side chains (Cunningham 1981). The half-life elimination is 4-12 hours and is dose-dependent (Cunningham 1981). Probenecid demonstrated no response in activation of PXR (Luo 2002 and Sinz 2006) and did not induce CYP3A4 in vitro (Luo 2002). When probenecid was co-administrated with carbamazepine (a CYP3A4 and CYP2C8 substrate) the AUC of carabamazepine decreased by 19%. This could indicate that probenecid might be an inducer of CYP3A4 or CYP2C8, or both of them (Cui 2008 and Kim 2005). The decrease in AUC is however, according to the U.S Food and Drug administration, too low for probenecid to considered as an inducer (FDA). Besides, carbamazepine is listed as an inducer of CYP3A4 (Hisaka 2010 and Pelkonen 2008), which means that there is a possibility that carbamazepine induced its own metabolism. It is listed as an inhibitor of CYP2C9 (Cheng 2010 and Flockhart 2007). A clinical study showed that co-administration of probenecid with naproxen reduced the clearance of naproxen conjugates and increased the excretion of desmethylnaproxen. The formation of desmethylnaproxen is the favoured pathway when renal clearance and conjugation of naproxen are inhibited. It does not have the same capacity as the usual pathway with the result that the half-life elimination and AUC increases (Runkel 1978). Naproxen is metabolised by CYP1A2 and CYP2C9 (Norsk Legemiddelhåndbok), and the data might therefore indicate that probenecid inhibit CYP1A2 or CYP2C9, or both.
Published experience
Probenecid has shown conflicting results of porphyrinogenicity in vitro (Disler 1982, Moore 1997 and Rifkind 1976).

References

  1. Scientific articles
  2. Luo G, Cunningham M, CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos. 2002 Jul;30(7):795-804. PMID 12065438. #4629
  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. Cui X, Thomas A, et al. Application and interpretation of hPXR screening data: Validation of reporter signal requirements for prediction of clinically relevant CYP3A4 inducers. Biochem Pharmacol. 2008 Sep 1;76(5):680-9. PMID 18647599. #4344
  5. Cunningham RF, Israili ZH, Dayton PG. Clinical pharmacokinetics of probenecid. Clin Pharmacokinet. 1981 Mar-Apr;6(2):135-51. #2403
  6. 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
  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. Kim KA, Oh SO, et al. Effect of probenecid on the pharmacokinetics of carbamazepine in healthy subjects. Eur J Clin Pharmacol. 2005 Jun;61(4):275-80. PMID 15915352. #4628
  9. 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
  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. Rifkind AB. Drug-induced exacerbations of porphyria. Prim Care. 1976 Dec;3(4):665-85. PMID 13442. #1739
  12. Runkel R, Mroszczak E, et al. Naproxen-probenecid interaction. Clin Pharmacol Ther. 1978 Dec;24(6):706-13. PMID 710028. #4630
  13. 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
  14. Drug reference publications
  15. Norsk legemiddelhåndbok. naproksen #2406
  16. Government bodies
  17. U.S Food and Drug Administration (FDA). #1450
  18. Drug interaction databases
  19. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). #1213
Similar drugs
Explore alternative drugs in similar therapeutic classes M04A / M04AB or go back.
 
© NAPOS 2024
An unhandled error has occurred. Reload 🗙