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Updated: May 22, 2026
10:44
Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures
Published on: March 28, 2017
Method for predicting human intestinal first-pass metabolism of UGT substrate compounds
Takako Furukawa1, Katsuhiro Yamano, Yoichi Naritomi
1Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., Ibaraki, Japan. takako-furukawa@astellas.com
Summary
Estimating intestinal glucuronidation impacts drug oral bioavailability (F). This study correlates intestinal UDP-glucuronosyltransferase (UGT) activity with drug absorption and availability (F(a)F(g)) to predict human drug candidates.
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Drug Discovery
Background:
- Intestinal glucuronidation significantly affects oral drug bioavailability (F).
- Accurate estimation of intestinal glucuronidation is crucial for selecting viable drug candidates.
- Understanding factors influencing F(a)F(g) aids in predicting in vivo drug performance.
Purpose of the Study:
- To investigate the relationship between intestinal glucuronidation and drug absorption and intestinal availability (F(a)F(g)).
- To estimate the impact of intestinal glucuronidation on F for drug candidates.
- To develop a method for predicting human F(a)F(g) based on in vitro data.
Main Methods:
- Assessed absorption and intestinal availability (F(a)F(g)) in animal models (rats, monkeys, dogs).
- Determined intrinsic clearance via UDP-glucuronosyltransferase (UGT) in intestinal microsomes (CL(int,UGT)).
- Correlated F(a)F(g) with CL(int,UGT) across species and applied to human data.
Main Results:
- F(a)F(g) was low in rats and monkeys but high in dogs, inversely correlating with high and low CL(int,UGT) respectively.
- Intestinal glucuronidation was identified as a key determinant of F(a)F(g) for the tested compounds.
- Human F(a)F(g) was predicted to be relatively high for the drug candidates.
Conclusions:
- The developed approach effectively estimates intestinal glucuronidation's impact on drug F.
- This method allows for semi-quantitative prediction of human oral bioavailability for drug candidates.
- The findings support informed selection of drug candidates with favorable pharmacokinetic profiles.
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