Glucuronidation: driving factors and their impact on glucuronide disposition

Area of Science:

• Pharmacology
• Drug Metabolism
• Biochemistry

Background:

• Glucuronidation is a major Phase II metabolic pathway for drugs and endogenous compounds.
• It is catalyzed by UDP-glucuronosyltransferases (UGTs), producing hydrophilic glucuronides.
• These glucuronides require efflux transporters for cellular exit and elimination.

Purpose of the Study:

• To elucidate the roles of UGTs, efflux transporters, and enterohepatic recycling in drug metabolism.
• To understand how these processes influence the disposition and systemic exposure of glucuronidated compounds.
• To highlight recent advances in the understanding of glucuronidation and transporter interplay.

Main Methods:

• Review of existing literature on glucuronidation, UGTs, and transporter functions.
• Analysis of evidence regarding biliary and enteric clearance of glucuronides.
• Examination of the impact of enterohepatic recycling on drug pharmacokinetics.

Main Results:

• UGTs control glucuronide formation, while transporters dictate their distribution and elimination.
• Hepatocytes efficiently clear gut-generated glucuronides via biliary excretion.
• Enterohepatic recycling involving gut microbes prolongs exposure to parent compounds and their glucuronides.

Conclusions:

• Drug elimination via glucuronidation is a complex process involving both UGTs and transporters.
• Transporter activity and enterohepatic recycling significantly modulate the pharmacokinetics and exposure of glucuronidated compounds.
• Understanding these interactions is crucial for predicting drug disposition and optimizing therapeutic outcomes.