Acute Porphyria Drugs

Acute Porphyria Drug Database

G02CB01 - Bromocriptine
Propably not porphyrinogenic
PNP
Rationale
Bromocriptine has been shown to be a mechanism-based inhibitor of CYP3A4 in vitro. It is most probably not an inducer or inhibitor of CYP enzymes in vivo. Risk for gastrointestinal adverse events in the form of constipation, vomiting and diarrhoea motivates vigilance against insufficient intake of food, especially of carbohydrate.
Chemical description
Bromocriptine is a dopamine receptor agonist and ergot peptide derivative.
Therapeutic characteristics
Bromocriptine is indicated for the treatment of Parkinsons disease, inhibition of lactation for medical reasons, hyperprolactinaemia, menstrual cycle disorders and female infertility, prolactinomas, acromegaly, premenstrual symptoms and benign breast disease. 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 constipation, vomiting and nausea. Other common side effects are headache, dizziness and drowsiness.
Metabolism and pharmakokinetics
Bromocriptine is extensively metabolised by CYP3A4 (SPC) to lysergic acid and peptides. It is a potent inhibitor of CYP3A4 in vitro (SPC) and has been reported to be a mechanism-based inhibitor of CYP3A4 in human liver microsomes (Zhou 2009). Bromocriptine inhibits the metabolism of tacrolimus, a CYP3A4 substrate (Norsk legemiddelhåndbok), and increase the exposure of tacrolimus in vitro (Christians 2002), but no quantitative assessment of this inhibition was given. An oral dose of 5 mg of bromocriptine results in a Cmax of 0.465 ng/ml (SPC and Wynalda 1997) or 0.7 nM. The maximal dose is 30 mg/day (SPC) which indicates that it will most probably not exceed 100 nM, the concentration needed to activate PXR and induce CYP enzymes. Wynalda (1997) also states that the plasma concentration of bromocriptine is too low to expect it to significantly inhibit or induce the metabolism of other drugs. Bromocriptine is not listed as an inducer or mechanism-based inhibitor of any major CYP enzymes (FDA, Hisaka 2010, Isoherranen 2009 and Pelkonen 2008) and no drug-drug interaction with bromocriptine as a perpetrator has been reported in the literature.
Published experience
Bromocriptine is listed as unsafe for use in acute porphyria because it has been shown to be porphyrinogenic in animals or in vitro systems (Moore 1997). Bromocriptine is listed as unsafe for use in acute porphyrias (Gorchein 1995).

References

  1. Scientific articles
  2. Christians U, Schmidt G, et al. Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes. Br J Clin Pharmacol. 1996 Mar;41(3):187-90. PMID 8866917. #4461
  3. Gorchein A. Treatment of Parkinsons disease in a patient with acute intermittent porphyria. Br J Clin Pharmacol. 1995 Jul;40(1):105-6. #1446
  4. 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
  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. 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
  7. Patteet L, Morrens M, et al. Therapeutic drug monitoring of common antipsychotics. Ther Drug Monit. 2012 Dec;34(6):629-51. #1449
  8. 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
  9. Zhou ZW, Zhou SF. Application of mechanism-based CYP inhibition for predicting drug-drug interactions. Expert Opin Drug Metab Toxicol. 2009 Jun;5(6):579-605. PMID 19466877. #1451
  10. Drug reference publications
  11. Norsk legemiddelhåndbok. Tacrolimus #1447
  12. Government bodies
  13. U.S Food and Drug Administration (FDA). #1450
  14. Summary of Product Characteristics
  15. Norwegian medicines agency. Summary of Product Characteristics (SPC). Bromokriptin. #1448
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