Acute Porphyria Drugs

Acute Porphyria Drug Database

L01BA01 - Methotrexate
Propably not porphyrinogenic
PNP
Rationale
Methotrexate is primarily excreted unchanged through the kidneys, and there is no evidence of CYP-metabolism. It does not inhibit nor induce CYP3A4. No reports of drug interactions indicating induction or inhibition of CYP2C9. However, side effects such as nausea, anorexia and vomiting may be potentially porphyrinogenic through reduction in caloric intake.
Chemical description
Methotrexate is a mixture containing at least 85% 4-amino-10-methylfolic acid, calculated on the anhydrous basis, and small amounts of related compounds. Structurally, the primary constituent of methotrexate differs from folic acid in the substitution of an amino group for a hydroxyl group in the pteridine nucleus and in the addition of a methyl group on the amino nitrogen between the pteroyl and benzoyl groups.
Therapeutic characteristics
Methotrexate, a folic acid antagonist, is an antineoplastic agent and immunosuppressant used in the management of acute lymphoblastic leukaemia, for Burkitts and other non-Hodgkins lymphomas, as well as in the treatment of choriocarcinoma and other gestational trophoblastic tumours, and for the adjuvant therapy of osteosarcoma and breast cancer. It may also be used in malignant neoplasms of the bladder and head and neck, and some other neoplasms. It is also used in the treatment of active rheumatoid arthritis and psoriasis. Methotrexate has two different ATC-codes, L01BA01 describes parenteral use, while methotrexate in oral formulations is classified in L04AX03. Common adverse reactions of methotrexate that can be confused with an acute porphyric attack are abdominal distress, vomiting and diarrhoea. Side effects such as nausea, anorexia and vomiting may be potentially porphyrinogenic through reduction in caloric intake.
Metabolism and pharmakokinetics
Methotrexate is excreted primarily unchanged by the kidneys via glomerular filtration and active transport. 58-92% of a single dose is excreted within 24 hours following IV administration. Methotrexate does not appear to undergo significant metabolism at low doses; after high-dose therapy the 7-hydroxy metabolite has been detected. When high-dose methotrexate is administered as a short intravenous infusion (4–6 h), most of the drug is cleared by the kidneys, but with longer infusions (24 h), about 40% of the drug is metabolised in the liver (Relling, 2000). Methotrexate did not activate PXR or increase CYP3A4 or CYP2B6 activity (Luo, 2002; Faucette, 2004; Sinz, 2006). Methotrexate did not affect the metabolism of vinblastine (Zhou-Pan, 1993). Methotrexate was not found to inhibit CYP3A4 activity (Baumhakel, 2001). No reports of drug interactions indicating induction or inhibition of CYP2C9.
Personal communication
Used uneventfully by 55 year old AIP woman (S. Thunell, Sweden). Uneventful use reported in one patient with AIP (C. Andersson, Sweden).
Published experience
Uneventful use reported in three patients with PV (Samuels, 1984).
IPNet drug reports
Uneventful use reported in 4 patients with acute porphyria, also uneventful use of methotrexate under the ATC-code L04AX03 is reported by 1 patient.

References

  1. Scientific articles
  2. Baumhäkel M, Kasel D, Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes. Int J Clin Pharmacol Ther. 2001;39(12):517-28. PMID 11770832. #4565
  3. Sinz, M, Kim, S, et al. Evaluation of 170 xenobiotics as transactivators of hPXR and correaltion to CYP 3A4 drug interactions. Curr Drug metabol 2006; 7:375-388. #1363
  4. Faucette SR, Wang H, et al. Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004;32(3):348-58. #1920
  5. Luo G, Cunningham M, et al. CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos. 2002;30(7):795-804. PMID 12065438. #4566
  6. Relling MV, Pui CH, et al. Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet. 2000;356(9226):285-90. PMID 11071183. #4567
  7. Samuels B, Bezwoda WR, et al. Chemotherapy in porphyria. S Afr Med J. 1984;65(23):924-6. #1924
  8. Zhou-Pan XR, Sérée E, et al. Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions. Cancer Res. 1993;53(21):5121-6. #1926
  9. Drug reference publications
  10. McEvoy GK, editor. Methotrexate. The AHFS Drug Information 2008. Bethesda, MD: American Society of Health-System Pharmacists; 2009. Electronic version (05.07.10). #1922
  11. Sweetman SC, editor. Martindale: The complete drug reference. Methotrexate. Pharmaceutical Press 2009. #1925
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