PHARMACOKINETICS OF INTRAVENOUS LUXABENDAZOLE IN RABBITS - INFLUENCE OF THE ENTEROHEPATIC CIRCULATION

Luxabendazole (LBZ) is a new benzimidazole carbamate chemotherapeutic agent, which has proved to be very effective against adult and immatur e stages of the major gastrointestinal nematodes, trematodes and cesto des. While information on the efficacy of LBZ in several animal specie s is available, there seems to be no published information describing the disposition kinetics in any of them. As a part of the clinical dev elopment of luxabendazole, the pharmacokinetics of a single intravenou s dose was investigated in parasite-free rabbits. Serial blood samples were collected at timed intervals for 12 h following administration o f the dose, and concentrations in plasma were determined by a sensitiv e and specific HPLC method. Published data on LBZ point to the possibl e existence of an enterohepatic cycle (EHC), and so, it seemed appropr iate to carry out two different forms of test. In the first, the possi bility of intestinal reabsorption of LBZ excreted via the bile was all owed for (Treatment 1), while in the second it was interrupted by the oral administration of activated charcoal (Treatment 2). In both cases the animals were given a single dose of 10 mg kg(-1) of LBZ intraveno usly (i.v). Comparison of the areas under the curve (AUCs) of LBZ conc entrations in plasma samples taken from the animals receiving each tre atment showed significant difference (p < 0.05). The given dose (10 mg kg(-1)) was converted in Treatment 1 to an effective dose of 13.9 mg kg(-1) through recycling of LBZ. With Treatment 2 a bicompartmental di stribution model for this drug was confirmed, together with high appar ent distribution volumes: V-c=1.87 L kg(-1), and V-beta = 7.09 L kg(-1 ). (C) 1998 John Wiley & Sons, Ltd.