Metabolism of praziquantel in kingfish Seriola lalandi

Abstract

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 ...

Pharmacokinetics and residue depletion of praziquantel in rice field eels Monopterus albus

“…PZQ is metabolized into hydro xy lated derivatives in kingfish; however, the predominant metabolite was different from that found in mammals (Tubbs et al 2008). Some studies of mammals have demonstrated that the site of hydroxylation is in the cyclohexyl ring (Lerch & Blaschke 1998, Meier & Blaschke 2001, Schepmann & Blaschke 2001; however, whether this is the case in fish is unknown.…”

Praziquantel degradation in marine aquarium water

“…Though the exact mechanism of its functionality is largely unknown ( Cioli et al, 2014 ; Olliaro, Delgado-Romero & Keiser, 2014 ), praziquantel (PZQ) has been utilized in the treatment of human schistosomiasis since 1984 ( Olliaro, Delgado-Romero & Keiser, 2014 ) and due to its efficacy, cost, safety and convenience of dispersal it has remained the primary treatment for this condition worldwide ( Cioli et al, 2014 ). It is well documented that PZQ is also useful in the treatment of other parasitic infections ( Chai, 2013 ) including those that parasitize animals ( Chisholm & Whittington, 2002 ; Forwood, Harris & Deveney, 2013 ; Iles, Archdeacon & Bonar, 2012 ; Ishimaru et al, 2013 ; Janse & Borgsteede, 2003 ; Masimirembwa, Naik & Hasler, 1993 ; Mitchell & Darwish, 2009 ; Mitchell, 2004 ; Schmahl & Mehlhorn, 1985 ; Schmahl & Taraschewski, 1987 ; Shirakashi et al, 2012 ; Steiner et al, 1976 ; Tubbs, Mathieson & Tingle, 2008 ; Tubbs & Tingle, 2006a ; Ward, 2007 ; Yamamoto et al, 2011 ).…”

“…In the aquarium industry, PZQ has been used to treat trematode, cestode and monogene infestations in both freshwater ( Forwood, Harris & Deveney, 2013 ; Iles, Archdeacon & Bonar, 2012 ; Mitchell & Darwish, 2009 ; Mitchell, 2004 ; Santamarina et al, 1991 ) and marine fish and elasmobranchs ( Chisholm & Whittington, 2002 ; Ishimaru et al, 2013 ; Janse & Borgsteede, 2003 ; Shirakashi et al, 2012 ; Thoney, 1990 ; Tubbs & Tingle, 2006a ; Tubbs & Tingle, 2006b ; Yamamoto et al, 2011 ). Though this drug can be administered to fish orally ( Forwood, Harris & Deveney, 2013 ; Janse & Borgsteede, 2003 ; Tubbs, Mathieson & Tingle, 2008 ; Tubbs & Tingle, 2006a ; Tubbs & Tingle, 2006b ), it is also common for it to be dissolved in the water in which the infested animal lives ( Chisholm & Whittington, 2002 ; Forwood, Harris & Deveney, 2013 ; Iles, Archdeacon & Bonar, 2012 ; Mitchell & Darwish, 2009 ; Mitchell, 2004 ). “Bath” treatments can range in duration from several minutes to several days to effectively remove parasites.…”

Preliminary Monitoring of Praziquantel in Water and Sediments at a Japanese Amberjack (Seriola quinqueradiata) Aquaculture Site

“…Small amounts of PZQ were detected from the water 3 days post-treatment, but the possibility of re-detection from water after that sampling point was thought to be low. Although environmental effects of PZQ metabolites should also be considered, the anthelmintic activity of PZQ metabolites in yellowtail kingfish was reported to be minor [18]. In the current preliminary study, no evidence regarding environmental impacts of oral PZQ administration in Japanese amberjack aquaculture was obtained, although further monitoring will be needed.…”