Acetaminophen pharmacokinetic and toxicological aspects: a review

Paracetamol (Tylenol®) is a widely used non-steroidal anti-inflammatory drug responsible for many cases of intoxication and liver failure. When taken orally, it is absorbed and begins to be digested in the stomach. Paracetamol is primarily metabolized by the liver via phase I and phase II enzymes (glucuronyltransferases and sulfotransferases). When present in excess in the body, it forms an active metabolite known as N-acetyl-para-benzoquinone-imine (NAPQI). This metabolite is a reactive species capable of binding to living cells and proteins causing injuries and adducts, which are largely responsible for damage, especially the liver. The study of paracetamol pharmacokinetics is important to understand its toxicity pathways and thus develop new therapies to prevent or minimize the damage caused by this drug. This review sought some of the most relevant works that address the pharmacokinetics of paracetamol to facilitate a general understanding of what has been discovered so far on the subject. This study also aims to make patients aware of the possible harm that can occur when this drug is indiscriminately used.

Overexpression of MRP3 in HeLa-UGT1A9 Cells Enhances Glucuronidation Capability of the Cells

Background: The interplay between phase II enzymes and efflux transporters leads to extensive metabolism and low systemic bioavailability of flavonoids. Objective: The study aims to investigate the dynamic interplay between multiple UGTs and multiple efflux transporters inside the cells. Methods: A new HeLa-UGT1A9-MRP3 cell was established to overexpress two dominant efflux transporters MRP3 and BCRP, and two UGT isoforms UGT1A9 and UGT1A3. The metabolism and glucuronides excretion for a model flavonoid genistein were determined in HeLa-UGT1A9-MRP3 cells and HeLa-UGT1A9-Con cells that overexpressed one UGT (1A9) and one efflux transporter (BCRP). Results: The excretion rate grew nearly 6-fold, cellular clearance of glucuronides increased about 3-fold, and a fraction of genistein metabolized (fmet) increased (14%, p<0.01) in the new cells. Small interfering (siRNA)-mediated MRP3 functional knockdown resulted in markedly decreases in the excretion rates (26%-78%), intracellular amounts (56%-93%), cellular clearance (54%-96%) in both cells, but the magnitude of the differences in HeLa-UGT1A9-Con cells were relatively small. Reductions in fmet values were similarly moderate (11%-14%). In contrast, UGT1A9 knockdown with siRNA caused large decreases in the excretion rates (46%-88%), intracellular amounts (80%-97%), cellular clearance (80%-98%) as well as fmet value (33%-43%, p<0.01) in both UGT1A9 cells. Comparisons of the kinetic parameters and profiles of genistein glucuronidation and UGT mRNA expression suggest that HeLa-UGT1A9-MRP3 has increased expression of both MRP3 and UGT1A3. Conclusion: The newly engineered HeLa-UGT1A9-MRP3 cells are an appropriate model to study the kinetic interplay between multiple UGTs and efflux transporters. It's a promising biosynthetic tool to obtain flavonoids glucuronides of high purity.

Stratification of Volunteers According to Flavanone Metabolite Excretion and Phase II Metabolism Profile after Single Doses of ‘Pera’ Orange and ‘Moro’ Blood Orange Juices

Large interindividual variations in the biological response to citrus flavanones have been observed, and this could be associated with high variations in their bioavailability. The aim of this study was to identify the main determinants underlying interindividual differences in citrus flavanone metabolism and excretion. In a randomized cross-over study, non-obese and obese volunteers, aged 19–40 years, ingested single doses of Pera and Moro orange juices, and urine was collected for 24 h. A large difference in the recovery of the urinary flavanone phase II metabolites was observed, with hesperetin-sulfate and hesperetin-sulfo-O-glucuronide being the major metabolites. Subjects were stratified according to their total excretion of flavanone metabolites as high, medium, and low excretors, but the expected correlation with the microbiome was not observed at the genus level. A second stratification was proposed according to phase II flavanone metabolism, whereby participants were divided into two excretion groups: Profiles A and B. Profile B individuals showed greater biotransformation of hesperetin-sulfate to hesperetin-sulfo-O-glucuronide, as well as transformation of flavanone-monoglucuronide to the respective diglucuronides, suggestive of an influence of polymorphisms on UDP-glucuronosyltransferase. In conclusion, this study proposes a new stratification of volunteers based on their metabolic profiles. Gut microbiota composition and polymorphisms of phase II enzymes may be related to the interindividual variability of metabolism.