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: alpha= 0.1650 +/- 0.0839, 0.1611 +/- 0.0298, 0.2312 +/- 0.0540 min (-1), and beta= 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<or= 0.05) in alpha, beta, total body clearance (Cl) and volume of distribution at steady state (V(ss)). The AUC increased significantly with the doses (249.7, 376.7 and 562.5 microg min ml (-1)). After non-compartmental analysis there were no significant differences in plasma elimination rate constant ( lambda), MRT and V(ss) as a function of dose, but these differences were significant for Cl, between 16 and 20 mg kg (-1), and AUC (one-way ANOVA, P<or= 0.05). The two-way ANOVA showed no significant differences between the values obtained for the three doses when lambda- beta, Cl, V(ss)and V(a)were compared while AUC showed significant changes. On the other hand, the pharmacokinetic analysis (compartmental and non-compartmental) showed significant differences in AUC, Cl, V(ss) and V(a), but there were no significant differences when lambda- beta 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.