Investigations into the metabolism of drugs used in aquatic animal therapy are useful for understanding the mechanisms of xenobiotic transformation systems and can aid the development of dosing regimens. This study investigated the metabolism of the synthetic anthelmintic praziquantel, which has application in helminthiasis treatment for several fish species including kingfish Seriola lalandi, a commercial aquaculture finfish species. At least 7 mono-or dihydroxylated derivatives of the parent compound were identified in kingfish after administration of a 150 mg kg -1 oral praziquantel dose, paralleling findings in mammals. The structure of one representative mono-hydroxylated species that was prominent in the skin, muscle, liver, kidney and plasma of kingfish was investigated using fragmentation experiments; this revealed that hydroxylation of the parent molecule occurred in the tetrahydroisoquinoline region of praziquantel, analogous with mammalian metabolites, but different to that of the active mammalian metabolite (trans -4-OH-praziquantel). The implications of these findings with regard to biotransformation systems for this drug in mammals and fish are discussed.KEY WORDS: Praziquantel · Anthelmintic · Xenobiotic · Metabolism · Kingfish · Seriola lalandi Resale or republication not permitted without written consent of the publisherDis Aquat Org 78: [225][226][227][228][229][230][231][232][233] 2008 Blaschke 2001). The major product of oxidative PZQ metabolism has been identified as the 4-hydroxycyclohexyl analogue (4-OH-PZQ), which may exist in cis or trans configuration (Kiec-Kononowicz et al. 1991); interestingly, the trans-variant of this metabolite, trans-4-OH-PZQ, has shown a degree of anthelmintic activity against the helminth Schistosoma mansoni, both in vitro and in vivo (Andrews et al. 1983, Xiao et al. 1991, Staudt et al. 1992.Several enzymes responsible for the hepatic metabolism of PZQ to hydroxylated species have recently been identified in mammals; these include several phenobarbitone-inducible members of the cytochrome 450 (CYP) family, namely CYP1A2, CYP2C19 and CYP3A4 (Giorgi et al. 2001, 2003, Li et al. 2003. Interestingly, a number of mammalian CYP homologues have also been identified in fish. A 400 bp cDNA fragment from mummichog Fundulus heteroclitus liver RNA was 57 to 70% identical to the corresponding region of mammalian CYP3A genes . Furthermore, appreciable amounts of CYP3A-like proteins have been found in several teleostean species . These findings raise the possibility that hydroxylated PZQ metabolites, similar to those produced by mammals and with potential anthelmintic activity, may be produced by fish dosed with this drug.The metabolism of xenobiotics such as PZQ are of interest in fish, particularly if biotransformation products contribute to the efficacy of a drug. During the development of an assay to describe the pharmacokinetics of orally administered PZQ in kingfish Seriola lalandi (Tubbs & Tingle 2006a,b), several metabolites were isolated using HPLC. One ...
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