Effect of Nutrition on Drug-Induced Liver Injury: Insights from a High-Fat Diet Mouse Model.

Objectives: Literature suggests that a high-fat diet (HFD) potentially increases the risk of chemical/drug-induced toxicity after an acute overdose. Drug/chemical-induced hepatotoxicity has been well studied, and the mechanism that regulates this toxicity has been extensively examined using different experimental animal models. Our study focuses on drug-induced hepatotoxicity in HFD-fed female Balb/C mice. This study addresses the effect of nutrition on the magnitude of acetaminophen (APAP)-induced hepatotoxicity at different time intervals. Materials and Methods: Female Balb/C mice, after the weaning period separated into two different groups, normal diet (ND) and HFD receiving groups; after 15 weeks, they were dosed with a single dose (300 mg/kg per os (p.o.) of APAP. Blood samples were collected at different time intervals (0, 6 and 24 hours), and liver samples were collected at the end time point. Liver injury parameters [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)], antioxidant assay (sodium dismutase, glutathione, and catalase), and histopathology study were conducted. Pharmacokinetic (PK) analysis was done using the RP-HPLC system and Phoenix WinNonlin 8.3 software. Results: APAP-induced liver injury decreased AST and ALT in the HFD group compared with the ND group at 6 and 24 hours (p < 0.01 and p < 0.001), respectively. Antioxidant enzyme levels remained constant in the HFD group, whereas histopathology showed remarkable changes. The PK's of APAP in HFD indicate lower plasma concentrations of APAP (p < 0.05), with two-fold higher clearance and volume of distribution. Conclusion: HFD significantly reduced susceptibility to APAP-mediated liver injury in Balb/C mice compared with ND mice. Our study mimics the clinical scenario where the same dose of the drug is prescribed to the normal and obese population. Our results suggest the potential need for dose titration to assess an individual's nutritional state in a clinical scenario.

The effect of nutritional status on the pharmacokinetic profile of acetaminophen.

Nutritional imbalance (low protein / high fat) is a public health problem affecting many people in developing and developed nations. Such an imbalance will influence pathophysiological homeostasis in individuals and thereby considerably impact drug pharmacokinetics. It was reported that short-term fasting increases acetaminophen exposure in healthy subjects, whereas no effect was observed after a high-fat diet. These findings suggest the necessity of considering nutritional status when assessing the risk of acetaminophen-induced hepatotoxicity. Additionally, the role of nutrition status on the pharmacokinetic profile of acetaminophen (APAP) at toxic doses is either scanty or not available. With this background, we aimed to compare the effects of nutrition status on the pharmacokinetic profile of APAP at a toxic dose in three different dietary regimens like - Normal diet (ND), Low protein diet (LPD), and High-fat diet (HFD). Balb/C female mice were divided into three groups after weaning, and for the next 15 weeks, they were fed with their respective diets (ND, LPD, and HFD). After that, mice were dosed with APAP (300 mg/kg p.o), and blood sampling was done at different time intervals and centrifuged at 3000 rpm for 5 min to collect plasma samples. Plasma samples were analyzed using the HPLC method. Data analysis was done by Non-compartment analysis using Phoenix WinNonlin 8.3 software. LPD group shows higher values of Cmax, tmax, t1/2, and AUC0-4, AUC0-x values than ND and HFD groups. Both Cmax and AUC follow the pattern of drug exposure where LPD > ND > HFD. In conclusion, nutrition in the diet alters APAP pharmacokinetic profile at a toxic dose in three different diet regimes. Further study on CYP450 concentration and activity is essential to understand the pharmacokinetics difference between these dietary regimens.