title: Effect of itraconazole on the pharmacokinetics of digoxin in guinea pigs.
abstract: The effect of itraconazole (ITZ) on the pharmacokinetics of digoxin (DGX) was investigated in guinea pigs. The plasma concentrations of DGX in guinea pigs following treatment with ITZ (20 mg/kg intraperitoneally (i.p.)) after intravenous (i.v.) administration of DGX (0.125 mg/kg) were significantly higher 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 percentage cumulative excretion (3.1%) of DGX in urine of the ITZ-treated group 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-treated group were significantly reduced, while the V(dss) was unaffected. The plasma unbound fraction of DGX (ranged 47-58%) in the ITZ-treated group was generally similar to that in the controls (50-57%). The blood-to-plasma concentration ratio of DGX (range 1.28-1.42) in the absence of ITZ did not change in the presence of ITZ. Based on these results, the pharmacokinetic interaction 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.
authors.affiliation: Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nishihara
authors.forename: J
authors.initials: J
authors.lastname: Hibino
authors.forename: H
authors.initials: H
authors.lastname: Kotaki
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.forename: T
authors.initials: T
authors.lastname: Iga
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D065607:Cytochrome P-450 Enzyme Inhibitors; D004077:Digoxin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D006168:Guinea Pigs; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male
chemical_list: D000935:Antifungal Agents; D001798:Blood Proteins; D002316:Cardiotonic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D017964:Itraconazole; D004077:Digoxin