Implicaciones de la variabilidad interindividual en la biotransformación del paracetamol en las reacciones de hipersensibilidad causadas por este fármaco

Résumé

Paracetamol is a widely used medication for treating fever and pain worldwide. While it is considered a safe drug, adverse reactions to paracetamol have increased in recent years. These reactions include selective hypersensitivity reactions, and the underlying mechanism is not well understood. In this Thesis, we study whether changes in the bioavailability of paracetamol or its metabolites may be associated with the development of hypersensitivity reactions to paracetamol. The major metabolites of paracetamol are APAP-G y APAP-S, formed atier conjugation. Additionally, oxidaon leads to the production of a toxic metabolite known as NAPQI, which is neutralized by binding to GSH, resulting in the formation of APAP-GSH, APAP-Cys and APAP-Merc. We also analyzed rare metabolites that could play a role in hypersensitivity etiopathogenesis. The results obtained in this thesis show that patients suffering from paracetamol hypersensitivity exhibit a distinct metabolic profile in terms of both, major and rare metabolites. Furthermore, the use of different metabolites, such as APAP-GSH and APAP-S, in the basophil activation test enhances the precision of this diagnostic method. The results also suggest an association between genetic and phenotypic factors with the pharmacokinetic profile of paracetamol and its metabolites, with parcular influence of sex, mutations in transporter genes (ABCB1), genes involved in paracetamol biotransformation (UGT2B15, SULT1A1 and CYB5A), and in the regeneration of GSH (CBS and CTH).