NETOBIMIN (NTB) is an anthelmintic prodrug which is converted into albendazole by the gastrointestinal microflora after oral admin- istration to sheep (Delatour et al 1986). Albendazole (ABZ) is oxi- dised, by liver microsomal systems, into its pharmacologically active metabolite, albendazole sulphoxide (ABZSO), and in a second step to albendazole sulphone (ABZSO 2 ), an inactive metabolite. The pharmacokinetic behaviour of netobimin and albendazole is well documented in sheep (Lanusse and Prichard 1990). The low solubility of benzimidazole drugs and their limited absorption from the gut, result in low bioavailability. Netobimin is an interesting prodrug since it can be prepared as an ionic salt with good water solubility. Fenbendazole (FBZ), another widely used benzimidazole in veterinary medicine, acts as competitive inhibitor of albendazole sulphoxidase activity when it is incubated in vitro using liver microsomal preparations with albendazole as substrate (FBZ inhibitory constant = 243 μM) (Galtier et al 1986). The present in vivo study was designed to describe the pharma- cokinetic parameters of albendazole metabolites in sheep, when different netobimin oral doses were co-administered with fenben- dazole (1·1 mg kg –1 equivalent to 375 μM). The aim of this work is to determine whether fenbendazole could be used to improve the pharmacokinetic profile of netobimin. Female Merino sheep weighing 48·5 ± 6·5 kg were used in this trial. Animals were parasite-free and fed with hay and water ad libitum. Sheep were allocated into two groups. The study was conducted in two phases: Phase I: animals were treated with netobimin (Hapasil ® , Schering Plough S.A., Madrid, Spain) by oral administration of 7·5 mg (six animals) and 20 mg kg –1 body weight (four animals). Phase II: After a wash-out period of one month, the same ani- mals were treated with the same formulations and dosages of neto- bimin plus 1·1 mg kg –1 of fenbendazole (Panacur ® , Hoechst lbérica S.A., Madrid, Spain). Fenbendazole was given in a suspension with netobimin. All treatments were administered as a single dose orally. Blood samples were collected from the jugular vein into heparinized vacutainers during 120 hours after treatment. Blood was cen- trifuged inmediately and plasma collected and frozen at –20°C until the time of drug analysis. Analysis of plasma for albendazole, albendazole sulphoxide and albendazole sulphone was carried out by high performance liquid chromatography (Redondo et al 1998). Parent netobimin was not detectable in the plasma samples (< 0·4 μg ml –1 ). These results are in accordance with data of Delatour et al 1986 following oral administration in sheep. Pharmacokinetic analysis for albendazole sulphoxide and alben- dazole sulphone were carried out by using PKCALC software with a non-compartmental model (Shumaker 1986). The pharmacokinetic parameters are presented as mean ± S.D. Mean pharmacokinetic parameters for each formulation were compared by analysis of variance (ANOVA). Whenever a significant F-value was obtained, a Newman-Keuls multiple range test was performed to indicate the order of significance. Values of P ≤ 0·05 were considered statisti- cally significant. The plasma concentration versus time profile of the major metabolite, albendazole sulphoxide, obtained by the administration of each formulation is shown in Fig 1. There was a clear difference in the curve profile after administration of netobimin at 7·5 mg kg –1 alone and the curve after coadministration with fenbendazole. However, in the case of the netobimin 20 mg kg –1 and netobimin plus fenbendazole, this difference was not observed and the plasma curve is similar to the control. The pharmacokinetic parameters of albendazole sulphoxide obtained with the different netobimin treatments are displayed in Table 1. Statistical comparison was car- ried out between each treatment of netobimin alone and with fen- bendazole. Netobimin and albendazole were efficiently converted by the ruminal flora and the hepatic metabolic system of the sheep, these prevented the detection of these two compounds in the plasma in all formulations and at all sampling times. The alteration of albendazole oxidative metabolism by the coad- ministration of fenbendazole resulted in significant changes in the pharmacokinetic patterns of albendazole sulphoxide in sheep. When 1·1 mg kg –1 of fenbendazole was used with a dosage of 7·5 mg kg –1 of netobimin, the area under the concentration–time curve (AUC 0-∞ ) of albendazole sulphoxide showed a 75·5 per cent increase from control value (AUC 0-∞ 34·43 ± 7·91 versus 60·33 ± 11·93 μg h ml –1 ), while there was no difference in the AUC 0-∞ ratio albendazole sulphone/albendazole sulphoxide from the control value (Table 1). The increase in the AUC 0-∞ of the albendazole sulphoxide could be the result of several mechanisms: firstly, it has been reported that fenbendazole causes inhibition of the albendazole sulphoxida- tion by liver microsomes in vitro because both drugs are biotrans- formed by the same enzyme system (Galtier et al 1986, Benchaoui and McKellar 1996). Albendazole is converted into albendazole Bioavailability of albendazole sulphoxide after netobimin administration in sheep: effects of fenbendazole coadministration. G. MERINO, A.I. ALVAREZ, P.A. REDONDO, J.L. GARCIA, O.M. LARRODÉ, J.G. PRIETO. Laboratory of Animal Physiology. Faculty of Veterinary. University of León. E24071, León, Spain. SUMMARY After oral co-administration of two dosages of netobimin (7·5 and 20 mg kg –1 with fenbendazole (1·1 mg kg –1 ) to Merino sheep, the AUC 0-∞ of albendazole sulphoxide at the lower dosage of netobimin, was significantly increased (75·5 per cent) from control value (34·43 ± 7·91 versus 60·33 ± 11·93 μg h ml –1 ). The pharmacokinetic parameters MRT and T1 / 2 were also increased: 18·96 ± 2·54 vs 26·44 ± 4·69 h and 10·31 ± 1·72 vs 22·28 ± 6·75 h respectively. No data corresponding to the higher dosage of netobimin (20 mg kg –1 ) were statistically different from control values. It is concluded that fenbendazole increases the bioavailability of albendazole sulphoxide in sheep at the 7·5 mg kg –1 dosage, and this may produce a potentiated anthelmintic action. 0034-5288/99/030281 + 03 $18.00/0 © 1999 W. B. Saunders Company Ltd SHORT COMMUNICATION Research in Veterinary Science 1999, 66, 281–283 Article No. rvsc.1998.0276, available online at http://idealibrary.com on