Amiodarone modulates pharmacokinetics of low‐dose methotrexate in rats

Abstract

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.

Alteration of Methotrexate Biliary and Renal Elimination during Extrahepatic and Intrahepatic Cholestasis in Rats

“…17) Briefly, the instrument was an Agilent 1100 series (Agilent, Palo Alto, CA, U.S.A.) chromatograph provided with a fluorescence detector (excitation, 350 nm; emission, 430 nm). Separation was achieved at 30°C using a Gemini C 18 , 110A, 4.6ϫ 150 mm column and a Gemini C 18 , 4ϫ3 mm pre-column (Phenomenex, Torrance, CA, U.S.A.).…”

Resveratrol modifies biliary secretion of cholephilic compounds in sham-operated and cholestatic rats

“…The total glutathione amount in the bile was calculated as the sum of the reduced and oxidized forms of glutathione. The concentration of azithromycin in bile was determined by a previously described HPLC method[ 19 ].…”

IL-1 receptor blockade alleviates endotoxin-mediated impairment of renal drug excretory functions in rats

“…Analytic procedures. The concentrations of AZT, citrulline/arginine, and nitrites/nitrates were determined by previously described HPLC methods (14). Biochemical analyses of serum and urine were performed on a Cobas Integra 800 and Cobas Mira Plus (Roche Diagnostics, Mannheim, Germany) according to the manufacturer's instructions.…”

“…Data were analyzed with Kinetica and MS Excel software. Pharmacokinetic parameters of intravenously administered AZT were calculated according to standard noncompartmental techniques (14). The area under the plasma concentration-time curve (AUC0-ϱ) was calculated from the sum of the AUC0-Tlast, estimated by the log-linear trapezoidal rule from time 0 to the time of the last measured concentration (Tlast), and the AUC was extrapolated to infinity (AUC Tlast-ϱ) and calculated as the last measured concentration divided by the elimination constant (K el), estimated on the basis of linear regression analysis.…”