Acute Porphyria Drugs

Acute Porphyria Drug Database

G03CA03 - Estradiol
Possibly porphyrinogenic
PSP
Important Information
This ATC-code G03CA03 includes several different routes of administration; transdermal, peroral and vaginal, and the different routes of administration have different porphyria safety classifications. Local treatment with estradiol, i.e. vaginal tablets and vaginal ring, is probably not porphyrinogenic, while systemic treatment, i.e. per oral tablets and transdermal patches, is considered as possibly porphyrinogenic.
Side effects
Common adverse reactions of estradiol depend on the route of administration. Common side effects that can be confused with an acute porphyric attack are abdominal pains, nausea and diarrhoea. These side effects may potentially be porphyrinogenic if leading to a decrease in carbohydrate intake. An in vitro study found that estrogens might directly activate ALAS-1 (Du Plessis 2009). In presence of estrogen, the estrogen receptor-alpha (ER-alpha) bound to estrogen receptor elements (ERE) in the ALAS-1 promotor resulting in an elevated transcription of ALAS-1 and thereby causing a subsequent increase in the rate of the entire heme synthesis pathway.
Rationale
Estrogens are potentially porphyrinogenic; however, hormone replacement therapy containing estradiol has been used uneventfully by 88 postmenopausal women diagnosed with acute porphyria. Postmenopausal women have a lower endogenous hormone level and a reduced risk of having an acute porphyric attack compared to women of fertile age. The decreased vulnerability after menopause may therefore explain a higher tolerance to estrogen replacement therapy. Local treatment with estradiol, i.e. vaginal ring and vaginal tablets, give a very low plasma concentration and liver exposure. Such administration of the drug is therefore considered as probably not porphyrinogenic. However, we cannot exclude the possibility that systemic estradiol treatment, i.e. peroral tablets and transdermal patches, might elicit an acute attack since the exposure of the liver is higher. One published report describes an acute attack in a postmenopausal woman diagnosed with AIP when using a transdermal patch containing estradiol. These forms of administration are therefore classified as possibly porphyrinogenic. The transdermal patch is preferred over per oral tablets as the percutaneous route avoids first pass effect in the liver.
Chemical description
Estradiol is a natural steroid hormone.
Therapeutic characteristics
Estradiol is used as hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women. The higher doses might also be used as prevention of osteoporosis in postmenopausal women. There are several routes of administration. Estradiol may be administered as a transdermal patch, a vaginal ring, peroral tablets or vaginal tablets. Half-life of estradiol is approximately 1 hour.
Hepatic exposure
During chronic administration of the 7.5 µg vaginal ring and 10 µg vaginal tablet plasma estradiol levels were increased but did not exceed the normal range for postmenopausale women, which is up to 20 pg/ml (Santen 2015). Transdermal patches releasing 25-100 µg/24 hours, gave a peak estradiol serum concentration of 25–105 pg/ml (SPC). Peroral administration of 2 mg estradiol valerate gave a serum concentration of 141 pg/ml (Cano 1999).
Metabolism and pharmakokinetics
Estradiol is predominantly metabolized in the liver to estrone and then to estriol (SPC). CYP1A2 and 3A4 are involved in the hydroxylation of estradiol to estriol, which is further glucuronidated. Estradiol and its metabolites are mainly excreted by the kidneys (SPC). Estradiol is not found to be an inhibitor of CYP2C9, CYP2C19 and CYP3A4, and compared to ethinyl estradiol, it is less likely to cause mechanism-based inhibition due to the lack of an acetylenic group (Laine 2003). Estradiol is listed as an activator of human PXR (Honkakoski 2003, Mnif 2007) and has been found to induce CYP2A6 in vitro (Higasi 2007). However, there are no CYP dependent drug interactions of significance with estradiol as perpetrator (Lexi-interact).
Published experience
It is from clinical observations well known that progestogens and estrogens have a role in precipitating acute porphyric attacks (Andersson 2003, Bonkovsky 2014, Kauppinen 1992).I n a retrospective population-based study, a total of 48 postmenopausal women diagnosed with AIP had used different forms of HRT containing estradiol for climacteric symptoms without precipitating acute attacks (Andersson 2003). A case report describes acute porphyric attacks in two postmenopausal women diagnosed with AIP when using transdermal patches. One of the women used a patch containing estradiol, while the other used a patch containing estradiol and norethisterone (Wetterberg 1995).
IPNet drug reports
Estradiol has been used uneventfully by 32 patients with acute porphyria. Estriol (a metabolite of estradiol) has been used uneventfully by 8 patients with acute porphyria.

References

  1. Scientific articles
  2. Anderson KE. LHRH analogues for hormonal manipulation in acute intermittent porphyria. Semin Hematol. 1989 Jan;26(1):10-5. PMID 2646719. #1496
  3. 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
  4. 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
  5. Cano A, Castelo-Branco C, et al. Effect of menopause and different combined estradiol-progestin regimens on basal and growth hormone-releasing hormone-stimulated serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3 levels. Fertil Steril. 1999 Feb;71(2):261-7. PMID 9988395. #4469
  6. 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
  7. Higashi E, Fukami T, et al. Human CYP2A6 is induced by estrogen via estrogen receptor. Drug Metab Dispos. 2007 Oct;35(10):1935-41. Epub 2007 Jul 23. PMID 17646279. #4470
  8. Honkakoski P, Sueyoshi T, et al. Drug-activated nuclear receptors CAR and PXR. Ann Med. 2003;35(3):172-82. #1499
  9. 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
  10. 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
  11. 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
  12. Santen RJ. Vaginal administration of estradiol: effects of dose, preparation and timing on plasma estradiol levels. Climacteric. 2015 Apr;18(2):121-34. PMID 25327484. #1501
  13. Wetterberg L, Olsson MB, et al. [Estrogen treatment caused acute attacks of porphyria]. Lakartidningen. 1995 May 24;92(21):2197-8, 2201. #1506
  14. Government bodies
  15. #1302
  16. Drug interaction databases
  17. Lexi-Interact in UpToDate. Estradiol: Drug interaction program. #1500
  18. Summary of Product Characteristics
  19. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). (Estradot). #1502
  20. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). (Estring). #1505
  21. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). (Progynova). #1503
  22. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). (Vagifem). #1504
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