Purpose <p>The purpose of this study is to quantify the contribution of individual UDP-glucuronosyl transferase (UGT) enzymes involved in the glucuronidation of icenticaftor, which is primarily glucuronidated in the human liver to two distinct glucuronide metabolites that are ultimately excreted in the urine.</p> Methods <p>The formation of icenticaftor-glucuronide in recombinant UGT systems was scaled with relative activity factor (RAF) of involved UGT enzymes to determine the fraction glucuronidation in human liver.</p> Results <p>Scaling of the glucuronidation activity of UGT enzymes in recombinant UGT systems demonstrated that hepatic UGT1A9 contributed to about two-third of the overall icenticaftor glucuronidation while the remaining was accounted by UGT2B7. Moreover, the predicted UGT-mediated clearance of icenticaftor, upon scaling the intrinsic clearance (CL_int) with RAF, correlates well with that estimated in humans.</p> Conclusion <p>Collectively, current data are indicative of the utility of activity-based scalars to predict fraction glucuronidation and clearance of icenticaftor in the clinic. UGT1A9 is identified as the major UGT enzyme in the glucuronidation of icenticaftor in human liver.</p>