Acute Porphyria Drug Database

D10AF52 - Erythromycin, Combinations
Propably not porphyrinogenic
PNP

Important Information
Limitations: This safety classification applies only to preparations containing a combination of the two drugs erythromycin and isotretinoin. The same ATC code (D10AF52) can in some countries be used for different combinations of erythromycin and other drugs, which in theory may or may not be porphyrinogenic. Please refer to the classification and monograph of each individual substance.
Rationale
Erythromycin is a mechanism-based inhibitor of CYP3A4 and an activator of hPXR. Isotretinoin, and its active metabolite ATRA, have been reported to activate the PXR/RXR heterodimer, to upregulate transcription of the CAR gene and to upregulate the transcription factor FoxO1. The additive effects of erythromycin and isotretinoin is porphyrinogenic if systemic exposure is significant. However, percutaneous absorption is insignificant and dermal application of this combination preparation is therefore probably not porphyrinogenic.
Chemical description
Erythromycin is a macrolide antibiotic Isotretinoin is a retinoic acid analogue (13-cis retinoic acid)
Therapeutic characteristics
Erythromycin in combination with isotretinoin is used in the treatment of moderate acne. It is a gel that is administered topically.
Hepatic exposure
The percutaneous absorption of isotretinoin is reported to be negligible, less than 2 % after long-term dermal application of isotretinoin 0.05 % (Thielitz 2008). Plasma concentrations of isotretinoin and erythromycin were below 5 ng/ml after topical application (SPC). This is equivalent to 0.016 µM and 0.007 µM for isotretinoin and erythromycin, respectively, and hepatic exposure is insignificant.
Metabolism and pharmacokinetics
Erythromycin is a mechanism-based inhibitor of CYP3A4 in vivo and an activator of hPXR, and is therefore classified as porphyrinogenic when used systemically (see monograph ATC-code: J01FA01). Isotretinoin is not suspected to be an inducer or a mechanism-based inhibitor of CYP450 enzymes. Isotretinoin and its active metabolite ATRA have been reported to activate the RXR nuclear receptor, which is a part of the PXR/RXR heterodimer responsible for the induction of the ALAS-1 gene transcription (Wang 2006). In addition, isotretinoin has been found to upregulate transcription of the hCAR gene (Saito 2010), and ATRA is found to upregulate the transcription factor FoxO1 (Melnik 2011) and hence releasing a cascade of gene transcriptions that may result in the activation of ALAS-1. Isotretinoin is classified as possibly porphyrinogenic when used systemically (see monograph ATC-code: D10BA01). In systemic use isotretinoin might possibly potentiate the porphyrinogenic effect of erythromycin. However, after topical application the percutaneous absorption and hepatic exposure of isotretinoin and erythromycin are negligible (SPC and Thielitz 2008). This dermatological preparation is therefore classified as probably not porphyrinogenic due to the topical administration.
IPNet drug reports
Uneventful use reported in 1 patient with acute porphyria.

References

  1. Scientific articles
  2. Yasuda K, Ranade A , et al. A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos. 2008 Aug;36(8):1689-97. #1377
  3. Melnik BC. Isotretinoin and FoxO1: A scientific hypothesis. Dermatoendocrinol. 2011 Jul;3(3):141-65 PMID 22110774. #1373
  4. Saito K, Kobayashi K, et al. Constitutive androstane/active receptor is a target of retinoic acid receptor in humans. Biochem Pharmacol. 2010 Jul 1;80(1):129-35. PMID 20211151. #4430
  5. Thielitz A, Abdel-Naser MB, et al. Topical retinoids in acne--an evidence-based overview. J Dtsch Dermatol Ges. 2008 Dec;6(12):1023-31. #1376
  6. Wang K, Mendy AJ, et al. Retinoids activate the RXR/SXR-mediated pathway and induce the endogenous CYP3A4 activity in Huh7 human hepatoma cells. Toxicol Sci. 2006 Jul;92(1):51-60. PMID 16632523. #4431
  7. Summary of Product Characteristics
  8. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). (Isotrexin). #1375

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