Acute Porphyria Drugs

Acute Porphyria Drug Database

A03FA01 - Metoclopramide
Propably not porphyrinogenic
PNP
Rationale
Metoclopramide is shown to be a substrate of CYP2D6 and possibly 3A4, as well as a mechanism based inhibitor of CYP2D6 in in-vitro studies. However, it does not inhibit other CYPs in vitro, and no drug interactions that indicate inhibition or induction of CYP 2C9 or 3A4 have been reported. Metoclopramide has been used to treat nausea during attacks of acute porphyria without adverse affects. While several case reports describe attacks of acute porphyria following the use of metoclopramide, often the attack was already in progress when the drug was taken. Also, most cases describe that the patients were exposed to other factors such as known porphyrinogenic drugs, starvation and/or pregnancy that could explain the attacks.
Chemical description
Metoclopramide hydrochloride is a synthetic substituted benzamide. The drug is a derivative of p-aminobenzoic acid related to procainamide, but differs structurally from procainamide by the presence of 5-chloro and 2-methoxy aryl substituents.
Therapeutic characteristics
Metoclopramide is an antiemitic used for the management of GI motility disorders, especially gastric stasis, for the management of gastroesophageal reflux, for the prevention of cancer chemotherapy-induced nausea and vomiting, and for the prevention of postoperative nausea and vomiting. It can be administered orally, rectally or by IM or direct IV injection, by IV infusion or using intranasal formulation. Raised serum prolactin levels have been observed during metoclopramide therapy: this may result in galactorrhoea, irregular periods and gynaecomastia. This side-effect may theoretically be beneficiary in some women due to the decreased levels of porphyrinogenic progesterone.
Metabolism and pharmakokinetics
Metoclopramide is metabolised in the liver, primarily by CYP2D6, but CYP3A4 and CYP1A2 may also be involved to some extent (Desta, 2002). 20-30 % of the dose is excreted in urine as unchanged drug. In vitro, metoclopramide is an inhibitor of CYP2D6 (Ki = 0.96 µM and Kinact = 0.026 /min), possibly a mechanism based inhibitor. The effect on other isoforms was negligible (Desta, 2002). Therapeutic use: no reports describing drug interactions that indicate induction or inhibition of CYP2C9 or 3A4.
Personal communication
One report of uneventful use (C Andersson, Sweden).
Published experience
One report of worsening of an attack of acute porphyria following the use of metoclopramide in a previously undiagnosed AIP woman, however she also was exposed for several other porphyrinogenic drugs, such as diazepam, diclophenac and phenytoin (Jose, 2008). Two reports of attacks/ worsening attacks of acute porphyria following the use of metoclopramide in pregnant, previously undiagnosed AIP-women. However, both the pregnancy itself and hyperemesis leading to starvation may have caused the attacks (Shenhav, 1997; Milo, 1989). One report of an attack following the use of metoclopramide for nausea (Doss, 1981). Kumar et al (2010) reports metoclopramide as a precipitating factor of attacks in 3 AIP patients admitted to an emergency ward, however all 3 were also using other drugs that are considered unsafe (pantoprazole, rabeprazole, diclofenac). One report of metoclopramide being used in the treatment of an acute attack (Gopinathan, 1990). Elder et al reports that they have
IPNet drug reports
Uneventful use reported in 6 patients with acute porphyria.

References

  1. Scientific articles
  2. Desta Z, Wu GM, Morocho AM, et al. The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6. Drug Metab Dispos. 2002 Mar;30(3):336-43. PMID 11854155. #4341
  3. Doss M, Becker U, et al. Drug safety in porphyria: risks of valproate and metoclopramide. Lancet. 1981 Jul 11;2(8237):91. PMID 6113463. #4342
  4. Elder GH, Hift RJ, et al. Authors reply in: Gorchein A. Metoclopramide and acute porphyria. Lancet. 1997 Oct 11;350(9084):1104. #1070
  5. Gopinathan VP. Acute intermittant porphyria presenting as PUO. The Journal of the Association of Physicians of India. 1990; 38(5):380. PMID 2387835. #1071
  6. Hift RJ, Meissner PN, et al. Variegate porphyria in South Africa, 1688-1996 - New developments in an old disease. South African Medical Journal 1997; 87(6):722-731). #1072
  7. Jose J, Saravu K,et al. Drug use in porphyria: a therapeutic dilemma. Singapore Med J. 2008 Oct;49(10):e272-5. PMID 18946596. #4343
  8. Kumar S, Sharma N, et al. Spectrum of emergency department presentation in patients of acute intermittent porphyria: Experience from a North Indian tertiary care center. Neurol India [serial online] 2010 [cited 2010 Jun 30];58:95-8. PMID 20228472. #4329
  9. Milo R, Neuman M,et al. Acute intermittent porphyria in pregnancy. Obstet Gynecol. 1989;73(3 Pt 2):450-2. #1075
  10. Shenhav S, Gemer O, et al. Acute intermittent porphyria precipitated by hyperemesis and metoclopramide treatment in pregnancy. Acta Obstet Gynecol Scand. 1997;76(5):484-5. #1076
  11. Drug reference publications
  12. McEvoy GK, editor. Metoclopramide. The AHFS Drug Information 2008. Bethesda, MD: American Society of Health-System Pharmacists; 2009. Electronic version (23.06.10). #1074
  13. Sweetman SC, editor. Martindale: The complete drug reference. Metoclopramide. Pharmaceutical Press 2009. #1077
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