Distribution of intraperitoneally injected diclofenac in brown trout (Salmo trutta f. fario)

Abstract

The detection of low levels of pharmaceuticals in aquatic environments has lately raised concerns regarding possible adverse effects of these highly active substances on aquatic organisms. The non steroidal anti inflammatory drug diclofenac (DCF) is one of the pharmaceutical substances regularly detected in surface waters and has lately been demonstrated to elicit adverse effects in salmonid species at environmentally relevant concentrations. The aim of the present study was to investigate the distribution of DCF in indigenous brown trout (Salmo trutta f. fario) following intraperitoneal (i.p.) injection of a single dose of 14 C labelled DCF. A distribution kinetic over 36 h provides information on possible accumulation of DCF in different organs as well as on DCF detoxification in trout, possibly enabling identification of sites of preferential toxicity. Approximately 57% of the total single DCF dose appeared in the bile 6 h after i.p. application. Subsequently, DCF was observed to undergo enterohepatic cycling with an amount of 14 C activity comparable to the 6 h bile values reappearing in bile 36 h after application. Results for 14 C activity in intestine and pylori support the observation of enterohepatic cycling with a small peak in intestine at 3 h post i.p. injection and a low peak in intestine and pylori at 6 h post i.p. injection, reflecting presence of the drug substance in bile. The highest activity in intestine was found 24 h post injection coinciding with low levels in bile, followed by a gradual decrease of activity in intestine mirroring the re uptake of DCF into bile. The finding of enterohepatic cycling of DCF in brown trout is suggestive of a prolonged retention of DCF in brown trout.

Diclofenac: New data on chronic toxicity and bioconcentration in fish

“…Similar fast depuration of DCF in fish was also observed in other studies 19, 24. The very low concentrations measured in the fish at the end of the depuration period made it difficult to assess if small amounts of radioactivity still remained in the fish after the 14-d depuration phase, as indicated by the fitted depuration curve.…”

“…The very low concentrations measured in the fish at the end of the depuration period made it difficult to assess if small amounts of radioactivity still remained in the fish after the 14-d depuration phase, as indicated by the fitted depuration curve. One reason for small amounts remaining might be enterohepatic circulation of DCF in fish, as was described by Hoeger et al 24.…”

Cyto‐genotoxicity and oxidative stress in common carp (Cyprinus carpio) exposed to a mixture of ibuprofen and diclofenac

“…In humans, the CYP2C9 family is known to mediate the biotransformation of IBP and DCF by hydroxylation to 2-or 3hydroxyibuprofen and 4-hydroxydiclofenac, respectively, 54,55 while the families CYP2C8, CYP2C18, CYP2C19, and CYP2B6 mediate DCF biotransformation to 5-hydroxydiclofenac. 56 Gomez et al 57 noted that 2-hydroxyibuprofen was the major metabolite identified TABLE 3 Pearson's correlation between biomarker values in the different tissues of C. carpio exposed to the mixture and ibuprofen and diclofenac concentrations in water from binary mixture exposure systems, at the various exposure times in in vitro metabolism studies on fish, while Hoeger et al 24 showed that DCF inhibits COX activity and therefore prostaglandin E2 synthesis in brown trout head kidney macrophages in vitro, thus confirming the existence in fish of the same mode of action reported previously in mammalian species. Also, IBP and DCF-derived acyl glucuronides have been shown to form covalent bonds with both intraand extracellular proteins, with toxicological consequences.…”

“…DCF induces kidney damage and affects reproduction and growth in Daphnia magna and D. longispira. [21][22][23] It also induces damage on kidney, gill, and other tissues in Salmo trutta f. fario, 24 while IBP significantly affects the growth of several bacterial and fungal species. 25 Furthermore, previous studies have reported that NSAIDs such as DCF, IBP, NPX, and PAR induce oxidative stress and genotoxicity in D. magna, Hyalella azteca, and Cyprinus carpio.…”

Uptake from water, biotransformation, and biliary excretion of pharmaceuticals by rainbow trout

“…After repeated oral exposure of trout to sulfadimethoxine, oxolic acid, and oxytetracycline, the halflife in blood ranged from 36 to 134 h [24]. Hoeger et al [25] determined that the body half-life of DCF in brown trout was 36 h after a single intraperitoneal injection. Resin acids and 4,5,6-trichloroguaiacol reached steady-state concentrations in fish bile within 24 and 144 h, respectively [19,26].…”