In vivo evaluation of drug-drug interactions linked to UGT inhibition: the effect of probenecid on dalcetrapib pharmacokinetics

Objective: To assess the effect of the UGT inhibitor probenecid on the pharmacokinetics of dalcetrapib, an investigational drug whose pharmacologically active thiol form undergoes glucuronidation (f(m) (UGT) >= 0.25). Materials and methods: A two-way crossover study in 20 healthy subjects. Subjects received a single 600 mg dose of dalcetrapib with or without probenecid (500 mg 4 times daily for 6 days). Results: AUC(infinity) and C-max of dalcetrapib thiol were increased by 14% and 21%, respectively, by co-administration of probenecid. Conclusions: This case study illustrates the difficulty in predicting clinically relevant drug-drug interactions for UGT substrates based only on the fraction metabolized by glucuronidation.