Paracetamol and Pain Modulation by TRPV1, UGT2B15, SULT1A1 Genotypes: A Randomized Clinical Trial in Healthy Volunteers

Background The influence of the genetic polymorphism of enzymes and receptors involved in paracetamol metabolism and mechanism of action has not been investigated. This trial in healthy volunteers investigated the link between paracetamol pain relief and the genetic polymorphism of 23 enzymes and receptors. Design This randomized double-blind crossover controlled pilot study took place in the Clinical Pharmacology Department, University Hospital, Clermont-Ferrand, France. Forty-seven Caucasian volunteers were recruited. The trial consisted of two randomized sessions one week apart with oral paracetamol or placebo, and pain changes were evaluated with mechanical pain stimuli. The genetic polymorphism of 23 enzymes and receptors was studied, and correlations were made with pain relief. All tests are two-sided with a type I error at 0.05. Results Paracetamol was antinociceptive compared with placebo (222 ± 482 kPaxmin vs 23 ± 431 kPaxmin; P = 0.0047), and the study showed 30 paracetamol responders and 17 paracetamol nonresponders. Responders were characterized by TRPV1rs224534 A allele, UGT2B15rs1902023 TT genotype, and SULT1A1rs9282861 GG genotype (P < 0.05 for all). These findings confirm for the first time the involvement of a specific TRPV1 rs224534 variant in paracetamol antinociception. They also reveal a new antinociceptive role for specific variants of hepatic phase II enzymes associated with paracetamol metabolism. Conclusions The study warrants larger clinical trials on these potential genomic markers of paracetamol analgesia in patients. Confirmation of the present findings would open the way to effective individualized pain treatment with paracetamol, the most commonly used analgesic worldwide.

Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective

After over 60 years of therapeutic use in the UK, paracetamol (acetaminophen,N-acetyl-p-aminophenol, APAP) remains the subject of considerable research into both its mode of action and toxicity.

The contribution of gut microflora to paracetamol metabolism

During the last decade, the important role of gut microflora as a special organ of the gastrointestinal system in the metabolism of drugs is well known. The aim of this study was to evaluate the role of the gut microecological population with enzymatic systems, especially beta-lyase, in the metabolism of paracetamol in mice. Two groups of 20 white male laboratory mice BALB/c, body weight 32+/-1.5 kg, were treated orally with neomycin sulphate (500 mg/kg in saline solution) and saline solution (10 ml/kg) twice daily for three days. After the treatment, the animals were given paracetamol dissolved in saline solution (200 mg/kg) intraperitoneally. The total amount of excreted paracetamol in 8 hours? collected urine was unchanged. A difference between treated and control mice was observed regarding a highly significant reduction in the excretion of 3-methylthiometabolites. A decrease in the excretion of thiomethyl metabolites was found in the control group compared to the experimental mice. Gut microflora had a great influence on the formation of metabolic precursors, thiomethyl-conjugates, and their oxidabile products. It is obvious that the ecosystem of gut microflora has an important role in the metabolism of paracetamol resulting in a significant reduction in the excretion of 3-methylthioparacetamol by urine, the glucuronide and sulphate.