Acute Porphyria Drugs

Acute Porphyria Drug Database

G03AA11 - Norgestimate and Ethinylestradiol
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). An in vitro study found that estrogens might directly activate ALAS-1 (Du Plessis 2009). In the presence of estrogen, the estrogen receptor-alpha (ER-alpha) binds to estrogen receptor elements (ERE) in the ALAS-1 promotor and results in an elevated transcription of ALAS-1 and thereby causing a subsequent increase in the rate of the entire heme biosynthesis pathway.
Rationale
Estrogens and 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
Ethinyl estradiol is a synthetic 20-acetylenic estradiol derivative. Norgestimate is a 19-nortestosterone derivate.
Therapeutic characteristics
Fixed-dose combined oral contraceptive. The half-life of norgestimate is about 30-67 hours, and the half-life of ethinyl estradiol is about 24 hours. Norgestimate ia a prodrug and is rapidly converted to the active metabolites norelgestromin and norgestrel (the levorotatory form is most biologically active) (Schindler 2008, SPC).
Metabolism and pharmacokinetics
Ethinyl estradiol is mainly metabolized via hydroxylation by CYP3A4 and CYP2C9 (Guengerich 1990, Wang 2004). Ethinyl estradiol is listed as an activator of hPXR by several references (Honkakoski 2003, Kretschmer 2005, Mnif 2007), but one in vitro study found that ethinyl estradiol only moderately transactivate hPXR, and this was seen at concentrations > 10 µM (Zhang 2007). Since this is well above concentrations obtained clinically the authors concluded that PXR activation is unlikely to be clinically relevant. Ethinyl estradiol contains an acetylenic group that has shown to cause mechanism-based inactivation of CYP enzymes (Ortiz 1980). In vitro studies suggest that ethinyl estradiol is a mechanism-based inhibitor of CYP3A4 through covalent attachment of the modified heme to the apoprotein (Guengerich 1988, Lin 2002) and CYP2B6 (Kent 2002). In vivo studies showed only minor and clinically insignificant effects on CYP 3A4 activity by oral contraceptives containing ethinylestradiol and progestin (Belle 2002, Palovaara 2000). The lack of observed significant effects on CYP 3A4 in vivo may partly be explained by PXR induction being counteracted and masked by a concurrent CYP inhibition, and this phenomenon has been discussed by Wei et al. for other drugs (Wei 2016). Ethinyl estradiol was found to be an in vitro inhibitor of CYP2C9 and CYP2C19 (Laine 2003), and the CYP2C19 inhibitory action is supported by in vivo studies (Hägg 2001, Palovaara 2003). Norgestimate is rapidly metabolised by first-pass (intestinal and/or hepatic) mechanisms to norelgestromin. Norelgestromin is further metabolized in the liver to norgestrel/levonorgestrel, as well as to other hydroxylated and conjugated metabolites (SPC). Both norelgestromin and norgestrel is metabolized by CYP3A4, with minor contributions from CYP2B6 and CYP2C9 (Ahire 2017). In vitro studies have shown that norgestimate and the metabolite levonorgestrel has potential to inhibit CYP3A4, and it is suggested that the inhibition could be mechanism-based (Back 1991). Progesterone and synthetic progestogens 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 Health 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 both ethinyl estradiol and the progestin component 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 5alfa-reductase steroid metabolism and it is suggested that this may lead to a diversion from the 5 alfa 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 and estrogens have a role in precipitating acute porphyric attacks (Andersson 2003, Kauppinen 1992, Bonkovsky 2014).

References

  1. Scientific articles
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  4. Ahire D, Sinha S et al. Metabolite Identification, Reaction Phenotyping, and Retrospective Drug-Drug Interaction Predictions of 17-Deacetylnorgestimate, the Active Component of the Oral Contraceptive Norgestimate. Drug Metab Dispos. 2017 Jun;45(6):676-685 PMID 28283499. #1472
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  6. 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
  7. 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
  8. 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
  9. Belle DJ, Callaghan JT, et al. The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity. Br J Clin Pharmacol. 2002 Jan;53(1):67-74. #1419
  10. 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
  11. 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. #1420
  12. Choi S-Y, Koh KH, et al. Isoform-spesific regulation of cytochrome P450 expression by estradiol and progesterone. Drug Metab Dispos 2013 Feb. 41:253-269. #1421
  13. Du Plessis N, Kimberg M, et al. Functional analysis of the 5´ regulatory region of the 5-aminolevulinate synthase (ALAS1) gene in response to estrogen. Cell Mol Biol (Noisy-le-grand). 2009 Jul 1;55(2):20-30. PMID 19656447. #4451
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  16. Hägg S, Spigset O, et al. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol. 2001 Feb;51(2):169-73. PMID 11259990. #4452
  17. 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
  18. 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
  19. 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. #1428
  20. 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
  21. Kent UM, Mills DE, et al. Effect of 17-alpha-ethynylestradiol on activities of cytochrome P450 2B (P450 2B) enzymes: characterization of inactivation of P450s 2B1 and 2B6 and identification of metabolites. J Pharmacol Exp Ther. 2002 Feb;300(2):549-58. PMID 11805216. #4453
  22. 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
  23. Laine K, Yasar U, et al. A screening study on the liability of eight different female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes. Pharmacol Toxicol. 2003 Aug;93(2):77-81. #1434
  24. Lin HL, Kent UM, et al. Mechanism-based inactivation of cytochrome P450 3A4 by 17 alpha-ethynylestradiol: evidence for heme destruction and covalent binding to protein. J Pharmacol Exp Ther. 2002 Apr;301(1):160-7. PMID 11907170. #4455
  25. Mnif W, Pascussi JM, et al. Estrogens and antiestrogens activate hPXR. Toxicol Lett. 2007 Apr 5;170(1):19-29. Epub 2007 Feb 16. PMID 17379461. #4456
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  27. Palovaara S, Kivistö KT et al. Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1-hydroxylation. Br J Clin Pharmacol. 2000 Oct;50(4):333-7. PMID 11012556. #1475
  28. Palovaara S, Tybring G, et al. The effect of ethinyloestradiol and levonorgestrel on the CYP2C19-mediated metabolism of omeprazole in healthy female subjects. Br J Clin Pharmacol. 2003 Aug;56(2):232-7. PMID 12895199. #4459
  29. 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
  30. 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
  31. Schindler AE, Campagnoli C et al. Classification and pharmacology of progestins. Maturitas. 2008 Sep-Oct;61(1-2):171-80 #1476
  32. 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
  33. 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
  34. Wang B, Sanchez RI, et al. The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol. Drug Metab Dispos. 2004 Nov;32(11):1209-12. Epub 2004 Aug 10. #1442
  35. 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
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  37. Zhang H, Cui D, et al. Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug. Clin Pharmacokinet. 2007;46(2):133-57. #1444
  38. Government bodies
  39. Norwegian medicines agency (NOMA). Find medicine. #1412
  40. Drug interaction databases
  41. Lexi-Comp in UpToDate. Ethinyl estradiol and norgestimate: Drug information. #1474
  42. Lexi-Interact, via UpToDate. #1152
  43. Micromedex® 2.0 (online). Drug Interactions). (23.08.2017). #1411
  44. The Danish Health and Medicines Authority. The drug interaction database. #1298
  45. Summary of Product Characteristics
  46. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Cilest. #1477
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