@article {Kotsuma1505, author = {Masakatsu Kotsuma and Taro Tokui and Stefan Freudenthaler and Kenji Nishimura}, title = {Effects of Ketoconazole and Quinidine on Pharmacokinetics of Pactimibe and Its Plasma Metabolite, R-125528, in Humans}, volume = {36}, number = {8}, pages = {1505--1511}, year = {2008}, doi = {10.1124/dmd.108.021394}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases. Pactimibe has two equally dominant clearance pathways forming R-125528 by CYP3A4 and M-1 by CYP2D6 in vitro. R-125528 is a plasma metabolite and is cleared solely by CYP2D6 despite its acidity. To evaluate contributions of the cytochrome P450 enzymes on the pharmacokinetics of pactimibe and R-125528 in humans, drug-drug interaction studies using ketoconazole and quinidine were conducted. Eighteen healthy male subjects were given a single dose of pactimibe sulfate without and with 400 mg of ketoconazole (q.d.). With the concomitant treatment, the area under the plasma concentration-time curve (AUC0{\textendash}inf) of pactimibe modestly increased 1.7-fold and AUC0{\textendash}tz of R-125528 decreased by 55\%. In addition, 17 healthy male subjects were given a single dose of pactimibe sulfate without and with 600 mg of quinidine (b.i.d.). With the concomitant treatment, the AUC0{\textendash}inf for pactimibe modestly increased 1.7-fold. On the other hand, the AUC0{\textendash}tz of R-125528 was markedly elevated 5.0-fold, although the AUC0{\textendash}inf could not be adequately defined because the terminal elimination phase of R-125528 was not obtained in the study period up to 72 h. As the fm CYP3A4 and fm CYP2D6 values of pactimibe estimated from in vitro studies were 0.40 and 0.33, respectively, AUC increase ratios of pactimibe were estimated to be 1.7 with ketoconazole and 1.5 with quinidine. These values were well in accordance with the values observed in this study. Moreover, the fm CYP2D6 of R-125528 estimated to be almost 1 would well explain the accumulation of R-125528 observed with the quinidine treatment. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/36/8/1505}, eprint = {https://dmd.aspetjournals.org/content/36/8/1505.full.pdf}, journal = {Drug Metabolism and Disposition} }