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 (fm UGT ≥ 0.25).


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∞ and Cmax 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.
Roche Products Ltd, UK.
Pau
P
Aceves Baldó
Judith
J
Anzures-Cabrera
Darren
D
Bentley
D000328:Adult; D000577:Amides; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D004952:Esters; D005260:Female; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D011339:Probenecid / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000493:pharmacokinetics*
D000577:Amides; D000924:Anticholesteremic Agents; D004952:Esters; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D014453:Glucuronosyltransferase; D011339:Probenecid