Dynamic Interplay of Age and Protein Malnutrition on the Pharmacokinetic Profile of Acetaminophen in Wistar Rats

Abstract

Objectives Age and protein malnutrition (PMN) are well-known determinants of drug pharmacokinetics. The combined influence of age and nutrition on the pharmacokinetics of acetaminophen (APAP) remains insufficiently explored; therefore, this study investigates the role of age and PMN on APAP pharmacokinetics. Materials and Methods Wistar rat weanlings were divided into four groups. Groups ND-5 (n = 6) and ND-18 (n = 6) were fed with normal diet (ND, 18% protein) and groups LPD-5 (n = 6) and LPD-18 (n = 6) were fed with low-protein diet (LPD, 10%) for 5 and 18 months, respectively. Blood samples were collected at different time intervals (0, 0.5, 1, 3, 6, 24, 36, and 48 hours), and plasma was separated and analyzed for APAP using high-performance liquid chromatography. Pharmacokinetic data was analyzed by the noncompartmental model using Phoenix WinNonlin 8.3 software. Results The pharmacokinetic parameters of APAP were elevated in both LPD groups compared with their age-matched controls. The average area under the curve was increased by approximately 131% (LPD-5) and 17.57% (LPD-18), and the average maximum plasma concentrations (Cmax) was increased by 33.5% (LPD-5) and 26.3% (LPD-18) compared with their respective age-matched controls. The average mean retention time was approximately 114% (LPD-5) and 17.4% (LPD-18) higher than their respective age-matched controls, whereas the clearance rate (Cl/F) and volume distribution (Vz/F) of the drug were significantly lower. Consequently, there was a 68.5% (ND-5) and 4.73% (ND-18) prolongation in the mean half-life of APAP. Conclusion The altered pharmacokinetics may arise from the intricate interplay of dietary and age influences on physiology, protein binding, and cytochrome P450enzyme activity/expression. However, the exact reason requires further investigation for a better understanding of vulnerable populations.