Acute Porphyria Drugs

Acute Porphyria Drug Database

G03AA07 - Levonorgestrel 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
Levonorgestrel is a 19-nortestosterone derivative and ethinyl estradiol is a synthetic 20-acetylenic estradiol derivative.
Therapeutic characteristics
Fixed-dose combined oral contraceptive. The half-life of levonorgestrel is 13-27 hours, and the half-life of ethinyl estradiol is about 24 hours.
Metabolism and pharmakokinetics
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 progestins (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). Levonorgestrel is mainly metabolized by CYP 3A4, with minor contributions from CYP2E1, CYP2C19 and CYP2C9 (SPC). Levonorgestrel possess an acetylenic group that has been reported to be involved in mechanism-based inhibition (Back 1991). 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 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).
IPNet drug reports
Uneventful use reported in 8 patients with acute porphyria. Reports of attacks: Three reports of acute attacks of porphyria requiring hospitalisation in previously undiagnosed AIP women. One report of acute attack of porphyria not requiring hospitalisation in previously undiagnosed AIP woman.

References

  1. Scientific articles
  2. Honkakoski P1, Sueyoshi T, et al. Drug-activated nuclear receptors CAR and PXR. Ann Med. 2003;35(3):172-82. #1426
  3. Kretschmer XC1, Baldwin WS. CAR and PXR: xenosensors of endocrine disrupters? Chem Biol Interact. 2005 Aug 15;155(3):111-28 #1432
  4. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989-1008. PMID 16176115. #1399
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. Guengerich FP. Metabolism of 17 alpha-ethynylestradiol in humans. Life Sci. 1990;47(22):1981-8. PMID 2273938. #1423
  14. Guengerich FP. Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol. 1988 May;33(5):500-8.’ PMID 3285175. #1457
  15. 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
  16. 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
  17. Innala E, Bäckström T et al. Women with acute intermittent porphyria have a defect in 5?-steroid production during the menstrual cycle. Acta Obstet Gynecol Scand. 2012 Dec;91(12):1445-52. #1427
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. Ortiz de Montellano P and Kunze KL. Self-catalyzed inactivation of hepatic cytochrome P-450 by ethynyl substrates. J Biol Chem. 1980 Jun 25;255(12):5578-85. PMID 7380828. #4457
  26. 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. #1439
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. 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
  36. Government bodies
  37. Norwegian medicines agency (NOMA). Find medicine. #1412
  38. Drug interaction databases
  39. Lexi-Interact, via UpToDate. #1152
  40. Micromedex® 2.0 (online). Drug Interactions). (23.08.2017). #1411
  41. The Danish Health and Medicines Authority. The drug interaction database. #1298
  42. Summary of Product Characteristics
  43. Norwegian medicines agency. Summary of Product Characteristics (SPC). Mirena. #1468
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