Upendra A. Argikar* Pages 304 - 309 ( 6 )
Background: Over the past two decades, saccharolactone has been routinely used in in vitro microsomal incubations, and sometimes in incubations with recombinant Uridine diphosphoglucuronosyl transferases (UGT) while investigating glucuronidation reactions. The addition of saccharolactone is aimed at completely inhibiting β- glucuronidases that may be present in the microsomes, in the anticipation of accurate identification and quantification of the formed glucuronide metabolites. Recent research has demonstrated that saccharolatone may not serve the intended objective, and may even lead to inhibition of certain UGTs.
Objective: This report investigates the historic evidence in the practice of saccharolactone addition in relation to β-glucuronidases and UGTs. The chemical nature and inhibition potency of saccharolactone are explored in an attempt to unravel the myth in its application. Finally, the collective evidence is discussed in an effort to provide guidance to drug metabolism scientists on the utilization of saccharolactone.
Conclusion: In-depth evaluation of the experimental evidence in the literature points toward a weak rationale for general in vitro application of saccharolactone. Furthermore, inhibition of recombinant or microsomal UGTs by saccharolactone may be model dependent. Overall, the integrated data suggests that saccharolactone should not be utilized in in vitro microsomal incubations with the objective of inhibiting β-glucuronidases.
Saccharolactone, saccharic acid, Uridine-diphosphoglucuronosyl transferases, glucuronidation, β-glucuronidases, glucuronides.
Pharmacokinetic Sciences, Global Biotransformation, Novartis Institutes for Biomedical Research, Cambridge, MA