Acute Porphyria Drugs

Acute Porphyria Drug Database

G03DA04 - Progesterone
Probably porphyrinogenic
PRP
Side effects
A suggested hypothesis for the porphyrinogenic potential of progestins (Thunell 2016) is that they activate the mPRalpha-PGRMC2 receptor complex (Thomas 2013), which is accompanied by heme binding (Rohe 2009), and may therefore result in a heme drain. A decreased cellular heme pool may then upregulate ALAS-1 (Besur 2014). In addition, the heme-sensing receptor, Rev-erb-alpha, will sense the decreased level of the regulatory heme pool and reduce its repressor effect on PGC-1alpha (Wu 2009). PGC-1alpha may then co-activate FoxO1 and NRF-1, with subsequent induction of the ALAS-1 gene (Handschin 2005).
Rationale
Progesterone is considered as a potentially porphyrinogenic substance and is known to have caused porphyric attacks in susceptible carriers of acute porphyria. Both pharmacodynamic and pharmacokinetic properties can explain the triggering effect in acute porphyria. Studies have shown that this hormone can affect CYP enzymes by induction. Although this effect is described to a limited extent in drug-drug interactions studies in general, it is likely that it has a role in a probable upregulation of the heme biosynthesis.
Chemical description
Progesterone is a steroid hormone.
Therapeutic characteristics
Progesterone is used in the treatment of dysfunctional uterine bleedings, amenorrhea, for prevention of endometrial hyperplasia caused by conjugated estrogen and as part of assisted reproductive technology treatment. Progesterone may be administered by the oral, intramuscular, subcutaneous, rectal or vaginal route.
Metabolism and pharmacokinetics
Progesterone activate PXR (Kliewer 1998 Honkakoski 2003). Progesterone is not listed as a significant inducer of CYP 3A4 in most interaction databases (Preissner 2010, NOMA, Lexi-Interact, The Danish Healt and Medicines Authority, Micromedex). Results from clinical studies suggest that the increased hormonal levels in pregnancy have the potential to alter hepatic cytochrome P450 drug metabolism (Anderson 2005). Also, in vitro studies have shown increased CYP mRNA after exposing hepatocytes to progesterone and estradiol levels equal to the high hormonal levels typically seen in the third trimester of pregnancy (Choi 2013). Hormonal therapy generally leads to a much lower plasma concentration relative to the levels of endogenous hormones in pregnancy and may explain the lack of observed significant effects of administered hormones on CYP 3A4 in vivo. Studies have shown that women with acute porphyria have an altered 5 alpha-reductase steroid metabolism and it is suggested that this may lead to a diversion from the 5 alpha reductase pathway to formation of 5beta steroid metabolites that may be more potent inductors of ALAS1 (Innala 2012, Anderson 1979, Jacobs 2005).
Preclinical data
It is from clinical observations well known that progestogens have a role in precipitating acute porphyric attacks (Andersson 2003, Kauppinen 1992, Bonkovsky 2014).
IPNet drug reports
One report of an attack requiring hospitalisation in a 31 year-old susceptible female with AIP. However there were other factors that could have contributed to the attack. Uneventful use reported in 11 patients with acute porphyria.

References

  1. Scientific articles
  2. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989-1008. PMID 16176115. #1399
  3. Anderson KE, Bradlow HL, et al. Studies in porphyria. VIII. Relationship of the 5 alpha-reductive metabolism of steroid hormones to clinical expression of the genetic defect in acute intermittent porphyria. Am J Med. 1979 Apr;66(4):644-50. PMID 433969. #4441
  4. Andersson C, Innala E, et al. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J Intern Med. 2003 Aug;254(2):176-83. PMID 12859699. #4440
  5. Besur S, Hou W, et al. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Nov 3;4(4):977-1006. #1380
  6. Bonkovsky HL, Maddukuri VC et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014 Dec;127(12):1233-41 PMID 25016127. #1511
  7. Choi S-Y, Koh KH, et al. Isoform-specific regulation of cytochrome P450 expression by estradiol and progesterone. Drug Metab Dispos 2013 Feb. 41:253-269. #1402
  8. Handschin C, Lin J, et al. Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell. 2005 Aug 26;122(4):505-15. PMID 16122419. #4434
  9. Honkakoski P, Sueyoshi T, et al. Drug-activated nuclear receptors CAR and PXR. Ann Med. 2003;35(3):172-82. #1499
  10. Innala E, Bäckström T et al. Women with acute intermittent porphyria have a defect in 5alpha-steroid production during the menstrual cycle. Acta Obstet Gynecol Scand. 2012 Dec;91(12):1445-52. PMID 22924787. #1406
  11. Jacobs MN, Nolan GT, et al. Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR). Toxicol Appl Pharmacol. 2005 Dec 1;209(2):123-33. PMID 15885729. #4472
  12. Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore). 1992 Jan;71(1):1-13. PMID 1549056. #1429
  13. Kliewer SA, Moore JT, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell. 1998 Jan 9;92(1):73-82. PMID 9489701. #4445
  14. Preissner S, Kroll K, et al. SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. PMID 19934256. #4466
  15. Rohe HJ, Ahmed IS, et al. PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. Pharmacol Ther. 2009 Jan;121(1):14-9. PMID 18992768. #4447
  16. Thomas P, Pang Y, et al. Enhancement of cell surface expression and receptor functions of membrane progestin receptor alpha (mPRalpha by progesterone receptor membrane component 1 (PGRMC1): evidence for a role of PGRMC1 as an adaptor protein for steroid receptors. Endocrinology. 2014 Mar;155(3):1107-19. PMID 24424068. #4473
  17. Thunell S. Genetik och metabola förlopp bakom den akuta porfyriattacken - Mer än hundra läkemedel är potentiellt livshotande vid akut porfyri. Lakartidningen. 2016 Sep 9;113. #1417
  18. Wu N, Yin L, et al. Negative feedback maintenance of heme homeostasis by its receptor, Rev-erb-alpha. Genes Dev. 2009 Sep 15;23(18):2201-9 #1469
  19. Government bodies
  20. Norwegian medicines agency (NOMA). Find medicine. #1412
  21. Drug interaction databases
  22. Lexi-Interact, via UpToDate. #1152
  23. Micromedex® 2.0 (online). Drug Interactions). (23.08.2017). #1411
  24. Summary of Product Characteristics
  25. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Utrogestan. #1515
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