Effect of itraconazole on the pharmacokinetics of digoxin in guinea pigs

The effect of itraconazole (ITZ) on the pharmacokinetics of digoxin (DGX) w as investigated in guinea pigs. The plasma concentrations of DGX in guinea pigs following treatment with ITZ (20 mg/kg intraperitoneally (ip)) after i ntravenous (iv) administration of DGX (0.125 mg/kg) were significantly high er than in the controls. The percentage cumulative excretion (6.9%) of DGX in bile of the ITZ-treated group up to 6 h after administration of DGX was significantly reduced (p < 0.05) compared with 10.5% in the control. The pe rcentage cumulative excretion (3.1%) of DGX in urine of the ITZ-treated gro up up to 6 h after administration was also one third that in the controls. The total, biliary, renal and metabolic clearances for DGX in the ITZ-treat ed group were significantly reduced, while the V-dss was unaffected. The pl asma unbound fraction of DGX (ranged 47-58%) in the ITZ-treated group was g enerally similar to that in the controls (50-57%). The blood-to-plasma conc entration ratio of DGX (range 1.28-1.42) in the absence of ITZ did not chan ge in the presence of ITZ. Based on these results, the pharmacokinetic inte raction between DGX and ITZ may be due not only to a reduction in the renal clearance but also to a reduction in the metabolic clearance of DGX by ITZ . Copyright (C) 1999 John Wiley & Sons, Ltd.