Comment

Treatment of paracetamol overdose: room for improvement?

Electrochemically treated nanoporous TiO₂ was employed as a novel electrode to assist in the photoelectrochemical degradation of acetaminophen and valacyclovir. The prepared electrode was characterized by scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). Cyclic voltammetry (CV), Mott-Schottky plots, ultraviolet-visible light (UV-vis) absorbance spectroscopy, and a total organic carbon (TOC) analyzer were employed to investigate the photoelectrochemical degradation of acetaminophen and valacyclovir. The results indicated no obvious removal of acetaminophen and valacyclovir over 3 h when separate photochemical degradation and electrochemical oxidation were employed. In contrast, acetaminophen and valacyclovir were rapidly eliminated via photoelectrochemical degradation. In addition, electrochemically treated nanoporous TiO₂ electrodes significantly enhanced the efficacy of the photoelectrochemical degradation of acetaminophen and valacyclovir, by 86.96% and 53.12%, respectively, when compared with untreated nanoporous TiO₂ electrodes. This enhanced performance may have been attributed to the formation of Ti³⁺, Ti²⁺, and oxygen vacancies, as well as an improvement in conductivity during the electrochemical reduction process. The effect of temperature was further investigated, where the activation energy of the photoelectrochemical degradation of acetaminophen and valacyclovir was determined to be 9.62 and 18.42 kJ/mol, respectively.

Acetaminophen (APAP) forms some reactive metabolites that can react with DNA. APAP is a potentially genotoxic drug and is classified as a Group 3 drug according to International Agency for Research on Cancer (IARC). One of the possible mechanisms of APAP genotoxicity after long term of use is that its reactive quinone imine (QI) metabolite of acetaminophen (NAPQI), can chemically react with DNA after glutathione (GSH) depletion. A quantum chemical study of the reactions between the NAPQI and deoxyguanosine (dG) or GSH was performed. Activation energies (ΔG^ǂ) for the reactions associated with the 1, 4-Michael addition were calculated on the M062X/6-311++G (d,p) level of theory. We modeled the reaction with dG as a multi-step process. The first step is rate-limiting (ΔG^ǂ = 26.7 kcal/mol) and consists of formation of a C–N bond between the C3 atom of the QI moiety and the N7 atom of dG. The second step involves proton transfer from the C3 moiety to the nitrogen atom of the QI with ΔG^ǂ of 13.8 kcal/mol. The depurination reaction that follows has a ΔG^ǂ of 25.7 kcal/mol. The calculated ΔG^ǂ for the nucleophilic attack of the deprotonated S atom of GSH on the C3 atom of the NAPQI is 12.9 kcal/mol. Therefore, the QI will react with GSH much faster than with DNA. Our study gives mechanistic insight into the genotoxicity of the APAP metabolite and will be useful for estimating the genotoxic potential of existing drugs with a QI moiety. Our results show that clinical application of APAP is safe, while in the case of severely depleted GSH levels APAP should be administered with caution.

An ultra performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) method was developed and validated to determine acetaminophen (AAP) and dihydrocodeine (DHC) in human plasma simultaneously. Plasma samples were prepared using protein precipitation with acetonitrile, the two analytes and the internal standard midazolam were separated on an Acquity UPLC BEH C18 column and mass spectrometric analysis was performed using a QTrap5500 mass spectrometer coupled with an electro-spray ionization (ESI) source in the positive ion mode. The MRM transitions of m/z 151.2 → 110.0 and m/z 302.3 → 199.2 were used to quantify for AAP and DHC, respectively. The linearity of this method was found to be within the concentration range of 50–10000 ng/mL for AAP, and 1–100 ng/mL for DHC in human plasma, respectively. The lower limit of quantification (LLOQ) was 50 ng/mL and 1 ng/mL for AAP and DHC in human plasma, respectively. The relative standard deviations (RSD) of intra and inter precision were less than 10% for both AAP and DHC. The analysis time of per sample was 1.0 min. The developed and validated method was successfully applied to a pharmacokinetic study of AAP (500 mg) with DHC (20 mg) capsule in Chinese healthy volunteers (N = 20).