Paracetamol Misuse and Dental Pain: Results from the French Observational DAntaLor Study.

AIMS: To evaluate the risk of hepatotoxicity due to unintentional paracetamol misuse in patients with acute dental pain. METHODS: A prospective multicenter observational survey was performed in patients consulting, without appointment, the odontology departments of three main French hospitals in the Lorraine region over a 3-month period. Patients were asked to fill out a medical questionnaire while seated in the waiting room. Those who completed 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 g 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-1.24h-1, or 100 mg.kg1.24h-1 over periods of 24, 48, and 72 hours, 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%. Paracetamol was self-medicated in 85.5% of the patients and misused by 6.0%. Clinical symptoms were observed in 1.6% of the patients with no paracetamol misuse. For patients consuming more than 4 g per day and experiencing mild unspecific clinical symptoms of hepatotoxicity, the suspected ingested dose category was below one of the three previously defined thresholds for 11.8% and was above for 40.0%. CONCLUSION: Patients with dental pain are at risk of paracetamol overdose and hepatotoxicity.

Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4.

Therapy with the antidepressant trazodone has been associated with several cases of idiosyncratic hepatotoxicity. While the mechanism of hepatotoxicity remains unknown, it is possible that reactive metabolites of trazodone play a causative role. Studies were initiated to determine whether trazodone undergoes bioactivation in human liver microsomes to electrophilic intermediates. LC/MS/MS analysis of incubations containing trazodone and NADPH-supplemented microsomes or recombinant P4503A4 in the presence of glutathione revealed the formation of conjugates derived from the addition of the sulfydryl nucleophile to mono-hydroxylated- and hydrated-trazodone metabolites. Product ion spectra suggested that mono-hydroxylation and sulfydryl conjugation occurred on the 3-chlorophenyl-ring, whereas hydration and subsequent sulfydryl conjugation had occurred on the triazolopyridinone ring system. These findings are consistent with bioactivation sequences involving: (1) aromatic hydroxylation of the 3-chlorophenyl-ring in trazodone followed by the two-electron oxidation of this metabolite to a reactive quinone-imine intermediate, which reacts with glutathione in a 1,4-Michael fashion and (2) oxidation of the pyridinone ring to an electrophilic epoxide, ring opening of which, by glutathione or water generates the corresponding hydrated-trazodone-thiol conjugate or the stable diol metabolite, respectively. The pathway involving trazodone bioactivation to the quinone-imine has also been observed with many para-hydroxyanilines including the structurally related antidepressant nefazodone. It is proposed that the quinone-imine and/or the epoxide intermediate(s) may represent a rate-limiting step in the initiation of trazodone-mediated hepatotoxicity.

Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4.

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 p-hydroxybuspirone 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.