Challenges and Opportunities with Predicting in Vivo Phase II Metabolism via Glucuronidation from in Vitro Data

Abstract

Glucuronidation is the most important phase II metabolic pathway which is responsible for the clearance of many endogenous and exogenous compounds. To better understand the elimination process for compounds undergoing glucuronidation and identify compounds with desirable in vivo pharmacokinetic properties, many efforts have been made to predict in vivo glucuronidation using in vitro data. In this article, we reviewed typical approaches used in previous predictions. The problems and challenges in prediction of glucuronidation were discussed. Besides that different incubation conditions can affect the prediction accuracy, other factors including efflux / uptake transporters, enterohepatic recycling, and deglucuronidation reactions also contribute to the disposition of glucuronides and make the prediction more difficult. PBPK modeling, which can describe more complicated process in vivo, is a promising prediction strategy which may greatly improve the prediction of glucuronidation and potential DDIs involving glucuronidation. Based on previous studies, we proposed a transport-glucuronidation classification system, which was built based on the kinetics of both glucuronidation and transport of the glucuronide. This system could be a very useful tool to achieve better in vivo predictions.

Keywords: Glucuronidation; PBPK; Prediction; Transport-Glucuronidation Classification System; Transporter.

Figure 1

Glucuronidation reaction (A) and preferred chemical structures for glucuronidation (B).

Figure 2

Transporters involved in the transport of glucuronide in hepatocytes (A) and enterocytes (B).

Figure 3

Transport-Glucuronidation Classification System and the representative compounds taking BCRP as an example. Compounds are classified based on the clearance by a transporter (Y-axis) and the clearance by glucuronidation (X-axis).