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Amiodarone modulates pharmacokinetics of low-dose methotrexate in rats

Leos Fuksa1, Eva Brcakova, Jolana Cermanova

  • 1Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, The Czech Republic.

Biopharmaceutics & Drug Disposition
|June 13, 2008
PubMed

Insights

Amiodarone significantly increases methotrexate (MTX) levels by impairing its elimination, raising toxicity concerns. However, azithromycin does not affect MTX pharmacokinetics, suggesting it is a safe co-medication for patients on low-dose methotrexate therapy.

Area of Science:

  • Pharmacology
  • Toxicology
  • Drug Interactions

Background:

  • Clinical observations indicate elevated methotrexate (MTX) plasma concentrations when co-administered with amiodarone or macrolide antibiotics.
  • Drug-drug interactions involving low-dose methotrexate (LDMTX) may lead to increased toxicity.

Purpose of the Study:

  • To investigate the impact of amiodarone and azithromycin on the renal and biliary elimination of MTX in a rat model.
  • To elucidate the mechanisms behind amiodarone-induced hyperbilirubinemia.

Main Methods:

  • Rats received a constant-rate intravenous infusion of MTX.
  • Concomitant single bolus intravenous injections of amiodarone or azithromycin were administered.
  • Renal and biliary clearance of MTX and conjugated bilirubin were measured.

Main Results:

  • Amiodarone reduced MTX biliary clearance by 27% and total clearance by 28%, increasing plasma MTX concentrations.
  • Amiodarone significantly decreased renal clearance of conjugated bilirubin by 3.3-fold, leading to elevated plasma bilirubin.
  • Azithromycin did not alter MTX pharmacokinetic parameters.

Conclusions:

  • This study is the first to demonstrate amiodarone's impairment of hepatic elimination of MTX.
  • Amiodarone-induced hyperbilirubinemia may result from increased bilirubin production and reduced renal clearance.
  • Azithromycin appears to be a safe concomitant medication for LDMTX therapy.

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