Intra-arterial pharmacokinetics and pulmonary first-pass of levamisole in rabbits

Abstract

The pharmacokinetics of levamisole after intra-arterial administration of 12.5, 16 and 20 mg kg−1 was investigated in rabbits. After compartmental analysis, the disposition of levamisole was well described by a two-compartment open model with mean values ± sd of: α= 0.1650 ± 0.0839, 0.1611 ± 0.0298, 0.2312 ± 0.0540 min −1, and β= 0.0118 ± 0.0022, 0.0125 ± 0.0026, 0.0120 ± 0.0024 min −1, for the three doses studied, respectively. There were no dose-related differences (one-way analyses of variance (ANOVA), P≤ 0.05) in α,β , total body clearance ( Cl) and volume of distribution at steady state (Vss ). The AUC increased significantly with the doses (249.7, 376.7 and 562.5 μ g min ml −1). After non-compartmental analysis there were no significant differences in plasma elimination rate constant ( λ), MRT and Vssas a function of dose, but these differences were significant for Cl, between 16 and 20 mg kg −1, and AUC (one-way ANOVA, P≤ 0.05). The two-way ANOVA showed no significant differences between the values obtained for the three doses when λ–β , Cl, Vssand Vawere compared while AUC showed significant changes. On the other hand, the pharmacokinetic analysis (compartmental and non-compartmental) showed significant differences in AUC, Cl, Vssand Va, but there were no significant differences when λ– β were compared. The slow clearance of levamisole by rabbit lung compared to a high pulmonary blood flow rate makes the possibility of significant first-pass lung metabolism unlikely in this animal species.