A high oxfendazole dose to control porcine cysticercosis: Pharmacokinetics and tissue residue profiles

https://doi.org/10.1016/j.fct.2012.07.023Get rights and content

Abstract

Oxfendazole (OFZ) is efficacious for porcine cysticercosis at 30 mg/kg. OFZ is not registered to be used at this dose. The assessment of the OFZ and metabolites [(fenbendazole sulphone (FBZSO2), fenbendazole (FBZ)] plasma pharmacokinetic and tissue residue profiles after its oral administration to pigs and the withdrawal period for human consumption were reported. Forty-eight pigs allocated into two groups received OFZ (30 mg/kg) orally as a commercial (CF) or as experimental formulation (SMF). Samples (blood, muscle, liver, kidney and fat) were collected over 30 days post-treatment and analyzed by HPLC. OFZ was the main compound recovered in plasma, followed by FBZSO2 and low FBZ concentrations. OFZ AUC0-LOQ (209.9 ± 33.9 μg·h/ml) and Cmax (5.40 ± 0.65 μg/ml) parameters for the CF tended to be higher than those for the SMF (AUC0-LOQ: 159.4 ± 18.3 μg h/ml, Cmax: 3.80 ± 0.35 μg/ml). The highest total residue (OFZ + FBZSO2 + FBZ) concentrations were quantified in liver, followed by kidney, muscle and fat tissue. FBZSO2 residue levels were the highest found in muscle (0.68 ± 0.39 μg/g) and fat (0.69 ± 0.39 μg/g). In liver and kidney the highest residues corresponded to FBZ (5.29 ± 4.36 μg/g) and OFZ (2.86 ± 0.75 μg/g), respectively. A withdrawal time of 17 days post-treatment was established before tissues are delivered for human consumption.

Highlights

► The pig plasma and tissue residue pattern after OFZ oral treatment at high dose used for cysticercosis was studied. ► The comparison of two different OFZ formulations was reported. ► OFZ and its metabolites FBZSO2 and FBZ were measured in the bloodstream after both treatments. ► Residual concentrations of OFZ and/or its metabolites FBZSO2 and FBZ were measured in all tissues. ► The OFZ use at this dose in pigs would require of an extended withdrawal time before deliver for human consumption.

Introduction

Taenia solium taeniasis/cysticercosis continues to be a costly scourge for most developing countries (Garcia and Del Brutto, 2005). Control of T. solium has progressed along the past 10 years and several tools have been introduced including new diagnostics, and an effective pig vaccine (TSOL18, University of Melbourne) (Gonzalez et al., 2003, Flisser et al., 2004, Gonzalez et al., 2005). Antiparasitic therapy of the intermediate host is crucial to eliminate the reservoir. Even in the presence of a vaccine, treatment is required to cover pigs which are already infected at the time of vaccination and can become a source for new infections. Oxfendazole (OFZ), or [5-(phenylsulphinyl)-1H-benzimidazole-2-yl] carbamic acid methyl ester, was first identified and manufactured by Syntex Research (Palo Alto, CA), and shown to have antihelminthic properties against larval and adult forms of gastrointestinal (GI) nematodes and cestodes in various animal species. OFZ is the active sulphoxide metabolite of fenbendazole (FBZ), a broad-spectrum benzimidazole methycarbamate (BZD). BZD anthelmintics are extensively metabolized in all mammalian species studied. FBZ and OFZ are metabolically interconvertible and the sulphoxide undergoes a second, slower oxidative step which forms the inactive metabolite fenbendazole sulphone (FBZSO2).

Different OFZ dose rates ranging between 2 and 10 mg/kg have been recommended in animals to control nematodes and cestodes. OFZ is highly efficacious for the treatment of porcine cysticercosis. It is well documented that OFZ (22.5% suspension, intended for use in cattle) when administered at a dose rate of 30 mg/kg, is effective for treatment of cysticercosis (Gonzalez et al., 1996, Gonzalez et al., 1997, Gonzalez et al., 1998). Several reasons made OFZ the drug of choice for the treatment of cysticercosis infected pigs. It is cheap, eliminates all cysts from the carcasses with a single dose (except for some residual cysts in the brain), is not associated with significant side effects, and the meat is useful for human consumption after treatment (Tsang et al., 1989, Gonzalez et al., 1996, Gonzalez et al., 1997, Gonzalez et al., 1998). As a consequence, OFZ has been used in several controlled trials and also in targeted and mass porcine chemotherapy programs in field conditions (Garcia et al., 2006, Assana et al., 2010). However, OFZ is not registered to be used at this high dose, neither for the cysticercosis treatment in pigs. One of the requirements for marketing authorizations for veterinary medicinal products is the availability of plasma pharmacokinetic (PK) and residue depletion profiles studies of the drug formulation in the species in which the new indication will be used. Pigs (and humans who could be also a target population for future uses of OFZ) are monogastric and thus pharmacokinetic parameters from ruminant hosts are poorly transferable. The goal of the present work was to study the OFZ and metabolites plasma disposition kinetics and residue profiles after its oral administration at 30 mg/kg to pigs using a 9.06% commercial formulation (Synanthic®, Pfizer, Mexico). A complementary goal of the current work included the comparison of the plasma PK of the standard commercial product (9.06%, Synanthic®, Pfizer, Mexico), with a locally formulated OFZ experimental preparation (22.5%) named as San Marcos Formulation (SMF). All together, the work reported here will contribute to: (a) establish a safe withdrawal period for human consumption of treated pig tissues; (b) for the purposes of medicinal product registration, and (c) provide a benchmark for the possible future development of improved formulations for pigs.

Section snippets

Experimental animals and treatment

Forty-eight (48) healthy male or female (Peruvian local ecotypes breed) 3–5 months old pigs purchased from commercial farms in Lima (Peru) were used in the experiment. Animals were kept indoors with food and water supplied ad libitum during the whole experimental period. All animal procedures and management protocols were conducted with international quality standards following the (VICH GL9 (GCP), 2000). Pigs were weighted and sorted to be randomly allocated into two treatment groups of 24 pigs

Plasma disposition kinetics

After OFZ administration as both the CF and SMF formulations at the single oral dose of 30 mg/kg to growing pigs, OFZ, FBZSO2 and FBZ were measured in plasma. The mean (±SEM) plasma concentration vs. time profiles of the three molecules for both treatments are shown in Fig. 1. OFZ was the main compound recovered in plasma between 2 and 96 h post-treatment. The inactive FBZSO2 metabolite was recovered between 2 and 72 h post-treatment. Low FBZ concentrations were quantified from 6 to 48 h

Discussion

Plasma concentration profiles reflect those attained for the different fluid/tissues where target parasite may be located. Consequently, its characterization contributes to understanding the relationship between drug concentration and clinical efficacy, which is useful to optimize parasite control. The OFZ plasma PK behavior in sheep (Marriner and Bogan, 1981) cattle (Prichard et al., 1985), goats (Hennessy et al., 1993) and horses (Sánchez Bruni et al., 2005), animal species in which OFZ was

Conflict of Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

We are grateful to Rosa Perales, Eloy Gonzales, and all the personnel of the UNMSM School of Veterinary Medicine of the Universidad Nacional Mayor de San Marcos in Lima, Peru, for their collaboration on study performance, to the staff of the School of Veterinary Science of the Universidad Nacional del Centro in Tandil, Argentina, for Laboratory analyses, and to Gianfranco Arroyo, DVM, Ph.D., for his help in organizing the study data and operational support. We also acknowledge the gift of 9.06%

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