Complexities of glucuronidation affecting in vitro in vivo extrapolation

Area of Science:

• Pharmacology
• Drug Metabolism
• Biochemistry

Background:

• Glucuronidation, mediated by UDP-glucuronosyltransferases (UGTs), clears diverse drugs and chemicals.
• UGT active sites within the endoplasmic reticulum create diffusional barriers, complicating in vitro-in vivo correlations.
• Latency phenomena, requiring detergents for maximal UGT activity, further hinder accurate clearance predictions.

Purpose of the Study:

• To highlight challenges in correlating in vitro and in vivo glucuronidation clearance.
• To discuss the utility of hepatocytes as an in vitro model for drug clearance evaluation.
• To explore drug-drug interactions involving UGTs and their regulatory mechanisms.

Main Methods:

• Review of existing literature on UGT-mediated drug clearance.
• Analysis of factors affecting UGT activity, including latency and transport processes.
• Comparison of UGT regulation with that of Cytochrome P450 (CYP) enzymes.

Main Results:

• Microsomal UGT activity underestimates in vivo clearance, with latency not being the sole cause.
• Hepatocytes show promise for early assessment of human drug clearance.
• UGT induction and inhibition can cause clinical drug-drug interactions, generally less severe than CYP-mediated ones due to high UGT Km values.

Conclusions:

• Predicting glucuronidation clearance in vitro is complex due to biological barriers.
• Hepatocytes represent a valuable tool for predicting in vivo drug clearance.
• Understanding UGT regulation is crucial for managing drug-drug interactions.