ABSTRACT:The therapeutic benefits of the antidepressant nefazodone have been hampered by several cases of acute hepatotoxicity/liver failure. Although the mechanism of hepatotoxicity remains unknown, it is possible that reactive metabolites of nefazodone play a causative role. Studies were initiated to determine whether nefazodone undergoes bioactivation in human liver microsomes to electrophilic intermediates. Following incubation of nefazodone with microsomes or recombinant P4503A4 in the presence of sulfydryl nucleophiles, conjugates derived from the addition of thiol to a monohydroxylated nefazodone metabolite were observed. Product ion spectra suggested that hydroxylation and sulfydryl conjugation occurred on the 3-chlorophenylpiperazine-ring, consistent with a bioactivation pathway involving initial formation of p-hydroxynefazodone, followed by its two-electron oxidation to the reactive quinone-imine intermediate. The formation of novel N-dearylated nefazodone metabolites was also discernible in these incubations, and 2-chloro-1,4-benzoquinone, a by-product of N-dearylation, was trapped with glutathione to afford the corresponding hydroquinone-sulfydryl adduct. Nefazodone also displayed NADPH-, time-, and concentration-dependent inactivation of P4503A4 activity, suggesting that reactive metabolites derived from nefazodone bioactivation are capable of covalently modifying P4503A4. A causative role for 2-chloro-1,4-benzoquinone and/or the quinone-imine intermediate(s) in nefazodone hepatotoxicity is speculated. Although the antianxiety agent buspirone, which contains a pyrimidine ring in place of the 3-chlorophenyl-ring, also generated phydroxybuspirone in liver microsomes, no sulfydryl conjugates of this metabolite were observed. This finding is consistent with the proposal that two-electron oxidation of p-hydroxybuspirone to the corresponding quinone-imine is less favorable due to differences in the protonation state at physiological pH and due to weaker resonance stabilization of the oxidation products as predicted from ab initio measurements.

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Aims: Dental pain is one of the main reasons for paracetamol consumption by the patients.The aim of the DAntaLor study was to evaluate the risk of hepatotoxicity due to unintentional paracetamol misuse occurring in patients with acute dental pain. Methods: A prospective multicentre observational survey was performed on patients consulting without appointment odontology department of three main French hospitals of the Lorraine region over a threemonth period. Patients were asked to fill a medical questionnaire while seating in the waiting room. Those who fulfilled the questionnaire, had dental pain and took paracetamol were included in the DAntaLor study. Misuse was defined as a daily dose of more than 4 grams of paracetamol per day. The risk of hepatotoxicity was considered high if the supposed ingested dose was above the threshold of 150 mg kg -1 24h -1 , 125 mg kg -24h -1 or 100 mg kg -24h -1 over a period of 24h, 48h or 72h, respectively. Hepatotoxicity was suspected in the presence of clinical symptoms. Results: Of the 1,810 patients consulting the odontology departments 741 were included in the study. Painkillers were used in 74.4% of the cases and paracetamol was taken by 81.7% of the patients. Paracetamol was self-medicated in 85.5% and misused by 6.0% of the patients. Clinical symptoms were observed in 1.6% of the patients with no paracetamol misuse. For patients consuming more than 4g per day, mild unspecific clinical symptoms of hepatotoxicity were experienced by 11.8% and 40.0% of the patients if the corresponding supposed ingested dose was below or above one of the three previously defined thresholds, respectively. Conclusion: Patients with dental pain are at risk of paracetamol overdose and hepatotoxicity.