Method for predicting human intestinal first-pass metabolism of UGT substrate compounds

Abstract

1. As intestinal glucuronidation has been suggested to generate the low oral bioavailability (F) of drugs, estimating its effects would be valuable for selecting drug candidates. Here, we investigated the absorption and intestinal availability (F_aF_g) in animals, and intrinsic clearance via UDP-glucuronosyltransferase (UGT) in intestinal microsomes (CL_int,UGT) for three drug candidates possessing a carboxylic acid group, in an attempt to estimate the impact of intestinal glucuronidation on F and select potential drug candidates with high F in humans.

2. The F_aF_g values of the three test compounds were low in rats and monkeys (0.16–0.51), and high in dogs (≥0.81). Correspondingly, the CL_int,UGT values were high in rats and monkeys (101–731 µL/min/mg), and low in dogs (≤ 59.6 µL/min/mg). A good inverse correlation was observed between F_aF_g and CL_int,UGT, suggesting that intestinal glucuronidation was a major factor influencing F_aF_g of these compounds.

3. By applying this correlation to F_aF_g in humans using human CL_int,UGT values (26.9–114 µL/min/mg), compounds 1–3 were predicted to have relatively high F_aF_g.

4. Our approach is expected to be useful for estimating the impact of intestinal glucuronidation on F in animals and semiquantitatively predicting human F for drug candidates.

Keywords::

• Intestinal metabolism
• in vitro–in vivo correlation
• UDP-glucuronosyltransferase (UGT)

Acknowledgments

The authors thank Dr. Fukushi Hirayama and Kazuhiko Ohne for providing compounds 1–3. The authors would also like to thank Yoshimitsu Nakajima and Masahiro Hirano for their help with the animal experiments, Kouichi Tanaka for his help with the PAMPA experiments, and Atsuko Hosoda for her help with metabolic profiling. The authors express their gratitude to thank Dr. Kazumi Hayashi, Dr. Kazuhiro Tetsuka, Fumihiro Nakamori, and Hiroyuki Moriguchi for useful discussions.

Declaration of interest: The authors report no declarations of interest.