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.

Retracted: Inhibiting the PI3K/Akt, NF-κB signalling pathways with syringic acid for attenuating the development of oral squamous cell carcinoma cells SCC131

“…Aberrant activation of PI3K/Akt pathways has been shown to promote several human cancers, which leads to the formation of apoptosis‐resistant tumour cells. [ 44 ] Elevated PI3K pathway causes phosphorylation of several downstream proteins which facilitates activation of Akt in many types of tumours. [ 10 ] In this present study, treatment with SRA downregulation of PI3K/Akt and NF‐κB creation associated with OSCC cells disrupts their interaction in SCC131 cell proliferation.…”

Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

“…Other non-hepatic UGT enzymes (UGT1A1, UGT1A7, UGT1A10) convert SN-38 to glucuronide (β-glucuronide conjugate) (SN-38G) secreted with bile [ 57 ]. Glucuronidation greatly increases the polarity of SN-38, promoting the elimination of drug from the body [ 58 ]. Irinotecan is transported to bile by a group of the ATP-binding cassette transporters (ABC transporters): ABCB1, ABCC1, ABCC2, and ABCG2 [ 59 ].…”

Synthesis and Preclinical Evaluation of the First Carbon-11 Labeled PET Tracers Targeting Substance P1–7

“…Glucuronidation is known as the most important phase II metabolic pathway responsible for the clearance of many endogenous and exogenous compounds. 37 Qualitative assessment using this MS/MS transition method of predicted metabolites with nonpolar plasma sample confirmed the glucorinated metabolite of [ 11 C] 1 ( Supporting Information Figure 5, green). In addition, the nonpolar plasma samples from the in vivo stability study of [ 11 C] 2 were reanalyzed ( Supporting Information Figure 5), all confirming postulated metabolites; a hydroxylation, oxidative deamination, or/and glucoronidation reaction.…”