Predicting the Pharmacokinetics of Acyl Glucuronides and Their Parent Compounds in Disease States

Acyl glucuronides are potentially reactive intermediates, which not only undergo hydrolysis and intramolecular acyl migration, but also bind irreversibly to plasma protein in vitro and in vivo. To evaluate the impact of renal failure, liver dysfunction and other disease states on the pharmacokinetics of acyl glucuronides and their parent compounds, a pharmacokinetic model has been established. The model has been successfully utilized to predict the pharmacokinetics of six compounds, diflunisal (DF), valproic acid (VPA), zomepirac (Z), suprofen (S), R-etodolac (R-ET), S-etodolac (S-ET), and their acyl glucuronides in various simulated disease states in experimental animals. Modeling studies revealed that altering the metabolic pathways of these compounds had significant impact on exposure and clearance of acyl glucuoninde. The simulation results also indicated that disease states that affect irreversible metabolic pathways other than glucuronidation may have major impacts on the apparent plasma clearance of the parent compound or exposure to the reactive acyl glucuronide as well. The study concluded that the model is sufficiently robust and applicable for pharmacokinetic studies of acyl glucuronides and their parent compounds in various disease states that may modulate drug clearance. The model is also applicable to understanding the complex disposition of other drugs subject to conjugation, especially those that can be reversible and undergo enterohepatic recycling, such as sulfation and glycine conjugation.