Abstract
The distribution, metabolism, excretion and hepatic effects of the human hepatotoxin fenclozic acid were investigated following single oral doses of 10 mg/kg to normal and bile duct-cannulated male C57BL/6J mice. Whole body autoradiography showed distribution into all tissues except the brain, with radioactivity still detectable in blood, kidney and liver at 72 h post-dose. Mice dosed with [14C]-fenclozic acid showed acute centrilobular hepatocellular necrosis, but no other regions of the liver were affected. The majority of the [14C]-fenclozic acid-related material recovered was found in the urine/aqueous cage wash, (49%) whilst a smaller portion (13%) was eliminated via the faeces. Metabolic profiles for urine, bile and faecal extracts, obtained using liquid chromatography and a combination of mass spectrometric and radioactivity detection, revealed extensive metabolism of fenclozic acid in mice that involved biotransformations via both oxidation and conjugation. These profiling studies also revealed the presence of glutathione-derived metabolites providing evidence for the production of reactive species by mice administered fenclozic acid. Covalent binding to proteins from liver, kidney and plasma was also demonstrated, although this binding was relatively low (less than 50 pmol eq./mg protein).
Highlights
Fenclozic acid (2-(4-chlorophenyl)-thiazol-4-ylacetic acid) (Myalex) was identified as a promising anti-rheumatic in the 1960’s that exhibited no adverse hepatic effects in pre-clinical animal tests or initial studies in man (Chalmers et al 1969a, b)
Potentially reactive acyl glucuronides are formed during the metabolism of fenclozic acid in vitro covalent binding in microsomal systems supplemented with UDPGA was lower than systems optimised for oxidative metabolism
In a previous study when fenclozic acid was administered to HRN mice at 10 mg/kg, where hepatic cytochrome P450s are non-functional, and there was no evidence of centrilobular necrosis, or any other effect on the liver
Summary
Fenclozic acid (2-(4-chlorophenyl)-thiazol-4-ylacetic acid) (Myalex) was identified as a promising anti-rheumatic in the 1960’s that exhibited no adverse hepatic effects in pre-clinical animal tests or initial studies in man (Chalmers et al 1969a, b). Fenclozic acid stands as an example of a drug candidate with a good pre-clinical safety profile and good efficacy that caused serious, dose-related, non-idiosyncratic adverse drug reactions (ADR’s) in man. Whilst such examples of human-specific ADRs are rare, they raise questions regarding the effectiveness of pre-clinical safety studies that would benefit from a thorough mechanistic investigation of the cause(s) of the toxicity. Recent studies showed that the bioactivation of fenclozic acid in vitro resulted in high levels of covalent binding to microsomal preparations supplemented with NADPH (Rodrigues et al 2013), but not UDPGA. The metabolic fate and hepatic effects of [14C]-fenclozic acid in normal and bile duct-cannulated male C57BL/6J mice have been investigated
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