Metabolism and pharmacokinetics of mebendazole in Japanese pufferfish (Takifugu rubripes)

Abstract

As a typical and broad-spectrum benzimidazole, mebendazole (MBZ) has long been used in human and veterinary medicine to treat parasitic infestations, and is widely employed in the aquaculture of Japanese pufferfish (Takifugu rubripes). However, there have been no studies examining the pharmacokinetic characteristics of MBZ in Japanese pufferfish. Furthermore, the presence of MBZ and its metabolites in animal-derived raw food represents a notable safety concern. Here, we investigated the metabolism of MBZ using a UPLC-Q-TOF system. Additionally, we evaluated the pharmacokinetics of MBZ and two metabolites, 2-amino-5(6)-benzoylbenzimidazole (MBZ-NH₂) and 5-hydroxymebendazole (MBZ-OH), in Japanese pufferfish following intramuscular injection of 20 mg/kg MBZ. We detected three metabolites of MBZ (M1–M3), among which, 2-amino-5(6)-(a-hydroxybenzyl) benzimidazole (M3) was detected in an aquatic animal for the first time. The plasma dispositions of MBZ, MBZ-NH₂, and MBZ-OH were characterized by low plasma clearance, medium distribution volume, and long terminal half-life. Moreover, these compounds were widely distributed in the muscle, from which they were rapidly cleared. The pharmacokinetics and metabolism of mebendazole in Japanese pufferfish are described for the first time in this study. Our findings provide a basis for the rational application of MBZ in Japanese pufferfish farming and contribute to our understanding of the metabolism of MBZ in cultured fish.

Keywords:

• Japanese puffer fish
• mebendazole
• pharmacokinetics
• metabolism
• food safety

Disclosure statement

No conflict of interest declared.

Animal welfare and ethics statement

The authors confirm that the ethical policies of the journal, as noted on the journal’s author guidelines page, have been adhered to and the appropriate ethical review committee approval has been received. The authors confirm that they have adhered to either US or European standards for the protection of animals used for scientific purposes. The animal experiments were performed in accordance with the regulations of the Animal Welfare and Research Ethics Committee of the Institute of Dalian Medical University’s Animal Care protocol Permit Number (Permit Number: SCXK2008-0002).

Data availability statement

The data and material of this study is available from the corresponding authors on reasonable request.

Additional information

Funding

This work was jointly supported by the High-level Talent Innovation Support Program of Dalian [2017RQ015], which provided for the project financially in purchase of reagent and materials; Innovation and Entrepreneurship Training Program for College Students [201912026091], which provided for the project financially in purchase of animals; A planned mentoring program project of the Liaoning Provincial Natural Science Foundation [2019-ZD-0170], which provided for the project financially in cost of using instruments to analyze samples.