Acute Porphyria Drugs

Acute Porphyria Drug Database

N07BC02 - Methadone
Propably not porphyrinogenic
PNP
Rationale
Methadone is not an inhibitor or an inducer of CYP3A4 in vivo. Risk for gastrointestinal adverse events in the form of vomiting, nausea, constipation and fatigue motivates vigilance against insufficient intake of food, especially of carbohydrate.
Therapeutic characteristics
Methadone is indicated for the treatment of dependence on opioid drugs. Very common and common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are vomiting, nausea, constipation and fatigue. Other common side effects are euphoria, hallucination, drowsiness and fatigue.
Metabolism and pharmakokinetics
Methadone is metabolised mainly by CYP3A4 with minor contribution by CYP2D6 and CYP2B6 (SPC). It is metabolised primarily via N-demethylation and the two most important metabolites are 2-ethyl-1,5-dimethyl-2,2-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrrolidinee (EMDP). Both are inactive (SPC and Tolson 2009). In vitro it has been shown to be extensively metabolised by CYP3A4 and to a lesser extent by 1A2, 2D6, 2D8, 2C9/2C8, 2C19 and 2B6 (Kapur 2011). In vitro data also indicates that methadone can induce CYP3A4 (Tolson 2009), but in vivo data shows the opposite. Methadone did not change the AUC or Cmax of rilpivirine (CYP3A4 substrate) when co-administrated, which indicates that it is not an inhibitor or an inducer of CYP3A4 (Crauwels 2013 and SPC). No drug interaction with methadone as a perpetrator has been shown, but the pharmacokinetics of methadone is affected by several drugs (Ferrari 2004). Gruber (2010) states that methadone is not a major inducer or inhibitor of CYP450 enzymes.
Published experience
Methadone is listed as safe for use in acute porphyria and has not been associated with human porphyric attacks (Moore 1997). Methadone is reported to be safely used in porphyria, or not produce experimental porphyria (Rifkind 1976) Methadone is listed as safe (Disler 1982, Kalman 1998).

References

  1. Scientific articles
  2. Disler, P. B., G. H. Blekkenhorst, et al. (1982). Guidelines for drug prescription in patients with the acute porphyrias. S Afr Med J 61(18): 656-660. #2817
  3. Ferrari, A., C. P. Coccia, et al. (2004). Methadone--metabolism, pharmacokinetics and interactions. Pharmacol Res 50(6): 551-559. #2818
  4. Kalman, D. R. and H. L. Bonkovsky (1998). Management of acute attacks in the porphyrias. Clin Dermatol 16(2): 299-306. #2820
  5. Moore, M. R. and R. J. Hift (1997). Drugs in the acute porphyrias--toxicogenetic diseases. Cell Mol Biol (Noisy-le-grand) 43(1): 89-94. #2822
  6. Rifkind, A. B. (1976). Drug-induced exacerbations of porphyria. Prim Care. 3(4): 665-685. #2824
  7. Crauwels H, van Heeswijk RP et al. Clinical perspective on drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor rilpivirine. AIDS Rev. 2013 Apr-Jun;15(2):87-101 PMID 23681436. #2816
  8. Gruber VA, McCance-Katz EF. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. Curr HIV/ AIDS Rep. 2010 Aug;7(3):152-60. PMID 20532839. #2819
  9. Kapur BM, Hutson JR et al. Methadone: a review of drug-drug and pathophysiological interactions. Crit Rev Clin Lab Sci. 2011 Jul-Aug;48(4):171-95.| PMID 22035341. #2821
  10. Tolson AH, Li H, et al. Methadone induces the expression of hepatic drug-metabolizing enzymes through the activation of pregnane X receptor and constitutive androstane receptor. PMID 19520773. #4707
  11. Summary of Product Characteristics
  12. Norwegian medicines agency. Summary of Product Characteristics (SPC). Methadon. #2823
  13. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Rilpivirine. #2825
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