Substrate selectivity of human intestinal UDP-glucuronosyltransferases (UGTs): in silico and in vitro insights

Abstract

The current drug development process aims to produce safe, effective drugs within a reasonable time and at a reasonable cost. Phase II metabolism (glucuronidation) can affect drug action and pharmacokinetics to a considerable extent and so its studies and prediction at initial stages of drug development are very imperative. Extensive glucuronidation is an obstacle to oral bioavailability because the first-pass glucuronidation [or premature clearance by UDP-glucuronosyltransferases (UGTs)] of orally administered agents frequently results in poor oral bioavailability and lack of efficacy. Modeling of new chemical entities/drugs for UGTs and their kinetic data can be useful in understanding the binding patterns to be used in the design of better molecules. This review concentrates on first-pass glucuronidation by intestinal UGTs, including their topology, expression profile, and pharmacogenomics. In addition, recent advances are discussed with respect to substrate selectivity at the binding pocket, structural requirements, and mechanism of enzyme actions.

• Active site residue
• bioavailability
• homology modeling
• metabolomics
• pharmacophore
• phase II metabolism
• QSAR