Preliminary kinetic data on flubendazole formulated as a hydroxypropyl-â-cyclodextrin aqueous solution for use in sheep.

CEBALLOS, L.; ALVAREZ, L.; TORRADO, J; SANCHEZ BRUNI, S.; MORENO, L.; LANUSSE, C

Torino, Italia

Congreso; 10th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2006

European Association for Veterinary Pharmacology and Toxicology

  Introduction: Benzimidazole (BZD) anthelmintics are widely used in human and veterinary medicine. The close relationship between their pharmacokinetic (PK) behaviour and clinical efficacy is well substantiated (1). However, the poor gastrointestinal absorption of BZD-methylcarbamates and the lack of water solubility which reduces flexibility for drug formulation, are still major obstacles. Flubendazole (FLBZ) is a broad-spectrum BZD methylcarbamate used for parasite control in pigs, chicken, turkeys and game birds. The high volume of distribution obtained for FLBZ in sheep (2) may be indicative of some advantages compared to other BZDs extensively used in ruminants. However, its administration as a micronized suspension to sheep resulted in reduced systemic availability for the parent drug and its main metabolites (2). Cyclodextrins (CDs) are used in pharmaceutical technology to enhance solubility of poor hydrosoluble compounds and a moderate effect on albendazole (ABZ) absorption in sheep has been reported (3). The comparative in vitro hydrosolubility of FLBZ and other close related BZD anthelmintics in the presence of hydroxypropyl-β-cyclodextrin (HPβCD) was evaluated in the current work. Based on those solubility results, the comparative PK behaviour of FLBZ (and its metabolites) intraruminally (i.r.) administered to sheep as either an aqueous CDs-based solution or a conventional carboximethylcellulose (CMC) suspension was assessed. Materials and Methods:  Solubility study: Drug solubility studies involving ABZ, mebendazole (MBZ) and FLBZ were performed in an aqueous solution (pH 1.2) containing HPβCD (10%). PK study: Six male Corriedale sheep (50.6 ± 6.0 kg) were used. In a crossover study the animals received either a HPβCD-FLBZ solution (HPβCD 10%, FLBZ 2%) (Group 1, n= 3) or a carboximethylcellulose (CMC)-FLBZ suspension (CMC 0.5%, FLBZ 2%) (Group 2, n= 3) by the i.r. route at the same dose rate (3.8 mg/kg). The treatment Groups were reversed after a 21-days washout period. Blood samples were collected between 0 and 72 h post-treatment. Plasma samples were analysed by HPLC as previously reported (2). Computerized kinetic analysis was carried out using conventional equations. Statistical comparison was performed using Student´s t-test. A value of P<0.05 was considered significant.  Results: FLBZ (2252 ± 552 µg/ml) aqueous solubility in CDs resulted markedly higher than that observed for MBZ (437 ± 47 µg/ml) and ABZ (921 ± 347 µg/ml). FLBZ, its reduced (R-FLBZ) and hydrolyzed (H-FLBZ) metabolites, were measured in plasma after both treatments. Low concentrations of H-FLBZ (close to the LOQ) were detected between 6-48 h post-treatment. Table 1 summarizes the main PK parameters obtained for FLBZ and R-FLBZ after administration of both FLBZ formulations.  Table 1: Plasma PK parameters (mean ± SD) obtained for flubendazole (FLBZ) and its reduced metabolite (R-FLBZ) after the i.r. administration of FLBZ (3.8 mg/kg) formulated as either a hydroxypropyl-β-ciclodextrin (FLBZ-HPβCD) solution or a carboximethylcellulose (FLBZ-CMC) suspension. FLBZ-HPβCD solution FLBZ-CMC suspension FLBZ R-FLBZ FLBZ R-FLBZ Cmax (µg/ml) 0.05 ± 0.02 0.25 ± 0.04 0.03 ± 0.01 0.14 ± 0.04* Tmax (h) 12.0 ± 0.00 10.9 ± 1.55 10.9 ± 1.73 12.2 ± 2.95 AUC0-t  (µg.h/ml) 1.83 ± 0.12 6.89 ± 1.68 1.53 ± 0.40 5.69 ± 3.11 * The value is statistically  different from the FLBZ-HPβCD solution Group at P<0.05 Discussion and Conclusions: A markedly higher aqueous solubility was obtained for FLBZ compared to other BZD anthelmintics in the presence of CDs under in vitro conditions. However, this formulation-based advantage in water solubility did not resulted in a differential PK behaviour compared to the treatment with the suspension. Contrarily to what was expected, the absorption-related PK parameters did not show any marked formulation-dependant effect. Only the Cmax value for the H-FLBZ metabolite was higher (P< 0.05) after administration of the novel CD-based preparation. Chemical stability of numerous foreign compounds is affected by ruminal flora. CDs are extensively metabolized in the human colon (4). It is then likely that after the i.r. administration of the CD-FLBZ complex, a ruminal microflora-mediated metabolic process may have hydrolized/destroyed the CDs structure. This may facilitate FLBZ release into the ruminal fluid, which could then be associated to the particulate ruminal material as it occurs after the treatment with the suspension formulation. Such a phenomenon may account to explain the equivalent FLBZ systemic availability obtained following administration of two pharmaceutically well distinguish formulations.   References 1. Lanusse and Prichard Drug Metab Rev 1993; 25: 235-279. 2. Moreno et al. J Vet Pharmacol Therap 2004; 27: 299-308. 3. Evrard et al. J Control Release 2002; 85: 45-50. 4. Challa et al. AAPS Pharm Sci Tech 2005; 6: 329-257. Acknowledgments: The authors acknowledge Dr. Kathleen Vlaminck (Janssen Animal Health, Beerse, Belgium) and Dr. Gustavo Viana (Janssen, BsAs, Argentina) for providing FLBZ/metabolites used in the present experimental work.