Clinical studies of low-dose methotrexate (LDMTX) pharmacokinetics document increased plasma concentrations of MTX after co-administration of the drug with amiodarone or macrolide antibiotics. As drug-drug interactions may increase the toxicity of LDMTX, a rat model was used to follow renal and biliary elimination of MTX during its constant-rate i.v. infusion and concomitant single bolus i.v. injections of amiodarone or azithromycin. The mean steady-state plasma concentration of 1.7+/-0.1 micromol/l was reached and the total clearance achieved 17.7+/-1.0 ml/min/kg. Administration of amiodarone decreased the biliary clearance of MTX to 73% of the control values (p<0.05). Correspondingly, the total clearance decreased to 72% and plasma MTX concentrations were augmented to 2.5+/-0.4 micromol/l (p<0.05). Amiodarone-treated rats exhibited a 3.3-fold decrease in the renal clearance (p<0.05) of conjugated bilirubin, which was associated with its increased plasma concentration. In contrast, azithromycin did not alter any of the MTX pharmacokinetic parameters. In conclusion, this is the first report describing the impairment of MTX hepatic elimination during co-administration with amiodarone. This study also provides new insight into acute amiodarone-induced hyperbilirubinaemia, where increased bilirubin production and decreased renal clearance may contribute to this effect. Importantly, azithromycin seems to be a safe co-medication during LDMTX therapy.

Department of Pharmacology Charles University Prague Faculty of Medicine in Hradec Kralove The Czech Republic

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