Acute Porphyria Drugs

Acute Porphyria Drug Database

H02AB02 - Dexamethasone
Possibly porphyrinogenic
PSP
Rationale
Dexamethasone is in several references listed as a weak or as a strong inducer of CYP 3A4. It is also listed as an inducer of multiple other CYP enzymes. Although drug-drug interaction databases warn against the concomitant use of dexamethasone with substrates of CYP 3A4 due to possible induction of their metabolism by dexamethasone, clinical evidence of such interaction is sparse. The CYP 3A4 induction potential of dexamethasone is suggested to be dose-dependent, and the effect also seems to vary greatly between different individuals. In spite of being listed as a safe drug in acute porphyria, a possible porphyrinogenic potential of dexamethasone under some circumstances cannot be ruled out. Rise in endogenous glucose production by dexamethasone might theoretically be an anti-porphyrinogenic effect.
Chemical description
Dexamethasone is a potent anti-inflammatory 9-fluoro-glucocorticoid
Therapeutic characteristics
Dexamethasone is used in the treatment of endocrine disorders, rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmic diseases, gastrointestinal diseases, respiratory diseases, hematologic disorders, neoplastic diseases, edematous states and cerebral edema. Route of administration depends on indication, may be taken orally or as injection. The glucocorticoid potency of dexamethasone is approximately equal to betamethasone. Dexamethasone has an elimination half-life of 3 to 5 hours. Dexamethasone binds to the glucocorticoid receptor and gives rise to endogenous glucose production. This may theoretically counteract possible porphyrinogenic pharmacokinetic effects, but the clinical outcome of this effect needs to be further evaluated.
Metabolism and pharmakokinetics
Dexamethasone is by several references and in drug-drug interaction databases listed as a substrate and an inducer of CYP 1A1, 1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 3A4, 3A5, (Pascussi 2000a, 2000b, Drugbank 2014, RXlist). In vitro studies with human hepatocytes have found dexamethasone to be a potent inducer of CYP3A4 (Pichard 1992). In a small clinical study where dexamethasone was administered together with the CYP 3A4 substrate triazolam, dexamethasone only had a small and not statistically significant effect on the pharmacokinetics of triazolam. It was mentioned by the authors that since glucocorticoids (including dexamethasone) themselves are metabolized by CYP 3A4, administration with another CYP 3A4 substrate might lead to a competitive inhibition of the metabolizing enzyme and thus complicating the measured degree of induction (Villika 1998). In a clinical study performed by Teo et al 2012, dexamethasone gave an increased occurrence of hepatotoxicity when taken concurrently with lapatinib. The suggested mechanism for this effect was induction of CYP 3A4 by dexamethasone leading to an increase in the formation of reactive metabolites from lapatinib. Another small clinical study showed that the degree of CYP 3A4 induction was subject for great intersubjective variability (McCune 2000). It is suggested that dexamethasone induces CYP3A4 in human hepatocytes both via direct activation of the Pregnane X receptor (PXR) at high concentrations (above 10 μM) and via activation of the glucocorticoid receptor which in turn induces transcription of PXR leading to increased expression of CYP3A4 at low concentrations. The induction of CYP3A4 by dexamethasone at low concentrations is considered modest whereas the induction response by dexamethasone at higher concentrations (bolus or stress conditions) results in much greater mRNA expression (Pascussi 2000). Different mechanisms for regulation of CYP enzymes by glucocorticoids are discussed (El-Sankary 2002, Pascussi 2002, 2003).
Published experience
Uneventfully used by one patient with VP (scarlett 1995).
IPNet drug reports
Uneventful use reported in 3 patients with acute porphyria.

References

  1. Scientific articles
  2. El-Sankary W1, Bombail V et al. Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein: DNA interaction distinct from the pregnane X receptor response element. Drug Metab Dispos. 2002 Sep;30(9):1029-34. #1578
  3. McCune JS1, Hawke RL, et al. In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone. Clin Pharmacol Ther. 2000 Oct;68(4):356-66. #1580
  4. Pascussi JM1, Drocourt L, et al. Dexamethasone induces pregnane X receptor and retinoid X receptor-alpha expression in human hepatocytes: synergistic increase of CYP3A4 induction by pregnane X receptor activators. Mol Pharmacol. 2000a Aug;58(2):361-72. #1583
  5. Pascussi JM1, Drocourt L, et al. Dual effect of dexamethasone on CYP3A4 gene expression in human hepatocytes. Sequential role of glucocorticoid receptor and pregnane X receptor. Eur J Biochem. 2001 Dec;268(24):6346-58. #1582
  6. Pascussi JM1, Gerbal-Chaloin S et al. Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. Mol Pharmacol. 2000b Dec;58(6):1441-50. #1584
  7. Pascussi JM1, Gerbal-Chaloin S,et al. The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochim Biophys Acta. 2003 Feb 17;1619(3):243-53. #1585
  8. Pichard L, Fabre I, et al. Effect of corticosteroids on the expression of cytochromes P450 and on cyclosporin A oxidase activity in primary cultures of human hepatocytes. Pharmacol. 1992 Jun;41(6):1047-55. PMID 1614409. #4486
  9. Scarlett JD, Corry J, et al. Cytotoxic chemotherapy and radiotherapy in a patient with breast cancer and variegate porphyria (VP). Aust N Z J Med. 1995 Dec;25(6):742-3. #1588
  10. Teo YL, Saetaew M, et al. Effect of CYP3A4 inducer dexamethasone on hepatotoxicity of lapatinib: clinical and in vitro evidence. Breast Cancer Res Treat. 2012 Jun;133(2):703-11. PMID 22370628. #4487
  11. Villikka K, Kivistö KT, et al. The effect of dexamethasone on the pharmacokinetics of triazolam. Pharmacol Toxicol. 1998 Sep;83(3):135-8. PMID 9783333. #4488
  12. Drug reference publications
  13. DrugBank. Dexamethasone. #1579
  14. RXList. #1587
  15. Sweetman SC, editor. Martindale: The complete drug reference. dexamethasone. (23.05.2014). #1589
  16. Summary of Product Characteristics
  17. Norwegian medicines agency. Summary of Product Characteristics (SPC). (Dexametason abcur). #1581
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