Acute Porphyria Drugs

Acute Porphyria Drug Database

G03AC01 - Norethisterone
Probably porphyrinogenic
PRP
Side effects
A suggested hypothesis for the porphyrinogenic potential of progestins (Thunell 2016) is that they activate the mPR alpha-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-1 alpha (Wu 2009). PGC-1 alpha may then co-activate FoxO1 and NRF-1, with subsequent induction of the ALAS-1 gene (Handschin 2005).
Rationale
Progestogens are considered as potentially porphyrinogenic substances and are 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 these hormones can affect CYP enzymes by induction and mechanism-based inhibition. Although these effects are described to a limited extent in drug-drug interactions studies in general, it is likely that they have a role in a probable upregulation of the heme biosynthesis.
Chemical description
Norethisterone (also known as norethindrone) is a 19-nortestosterone derivative.
Therapeutic characteristics
Progestogen-only oral contraceptive The half-life of norethisterone is 5-12 hours
Metabolism and pharmakokinetics
Norethisterone is mainly metabolized by CYP3A4, with minor contribution from CYP2C19 (Korhonen 2008). Norethisterone is partly metabolised to ethinylestradiol after oral administration of norethisterone or norethisterone acetate in humans. This conversion results in an equivalent dose of about 4-6 µg ethinylestradiol per 1 mg orally administered norethisterone / norethisterone acetate (SPC). Norethisterone has shown weak inhibition of CYP 2C9 In vitro (Korhonen 2008). Norethisterone also possesses an acetylenic group that has been reported to be involved in mechanism-based inhibition (Back 1991). White et. al (1977) reported that norethisterone and ethinyl estradiol caused loss of CYP450 enzymes and an increase in ALAS-1 activity in the liver. However, the study was performed in vitro and in rats and the results cannot be extrapolated to humans. Progesterone and synthetic progestagens activate PXR (Kliewer 1998). Progestogens and estradiol are not listed as significant inducers 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. However, since progestin have the potential to induce ALAS1 through PXR activation and at the same time cause mechanism-based inhibition of CYP 3A4, this may explain the absence of observed pharmacokinetic drug-drug interactions. For an evaluation of the porphyrinogenicity of these drugs it is important to realize that the inhibitory effect can mask the inductive power and that an increased de novo synthesis of CYP3A4 can take place irrespective of negative results from in vivo DDI-studies. The effects of concomitant induction and inhibition have in general been discussed by Wei et al. for other drugs (Wei 2016). Since CYP3A4 quantitatively is the largest CYP isoenzyme, an increased de novo synthesis of CYP3A4, although masked, will give an upregulation of ALAS-1and thereby a higher flux through the heme biosynthesis. Such a mechanism can possibly in part explain the observed porphyrinogenic effects of these drugs. 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).
Published experience
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
Uneventful use reported in 3 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. Back DJ, Houlgrave R, et al. Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes. J Steroid Biochem Mol Biol. 1991 Feb;38(2):219-25. PMID 2004043. #4442
  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. 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
  7. 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
  8. Innala E, Bäckström T et al. Women with acute intermittent porphyria have a defect in 5 alpha-steroid production during the menstrual cycle. Acta Obstet Gynecol Scand. 2012 Dec;91(12):1445-52. PMID 22924787. #1473
  9. Jacobs MN, Nolan GT, Hood SR. Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR). Toxicol Appl Pharmacol. 2005 Dec 1;209(2):123-33. PMID 15885729. #1408
  10. 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
  11. Korhonen T, Turpeinen M, et al. Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone. J Steroid Biochem Mol Biol. 2008 May;110(1-2):56-66. PMID 18356043. #4462
  12. Preissner S, Kroll K, rt 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. #4409
  13. 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
  14. Thomas P, Pang Y, et al. Enhancement of cell surface expression and receptor functions of membrane progestin receptor alpha (mPR alpha) 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. #4463
  15. 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
  16. Wei Y, Tang C, et al. A Molecular Aspect in the Regulation of Drug Metabolism: Does PXR-Induced Enzyme Expression Always Lead to Functional Changes in Drug Metabolism? Curr Pharmacol Rep. 2016 Aug;2(4):187-192. PMID 27795941. #4450
  17. White IN, Muller-Eberhard U. Decreased liver cytochrome P-450 in rats caused by norethindrone or ethynyloestradiol. Biochem J. 1977 Jul 15;166(1):57-64. PMID 901418. #1466
  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). Primolut N. (Last edition: 29.07. 2015). #1483
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