Effect of ABCB1 polymorphisms and atorvastatin on sitagliptin pharmacokinetics in healthy volunteers
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The objectives of this study were to determine if ABCB1 polymorphisms are associated with interindividual variability in sitagliptin pharmacokinetics and if atorvastatin alters the pharmacokinetic disposition of sitagliptin in healthy volunteers.
In this open-label, randomized, two-phase crossover study, healthy volunteers were prospectively stratified according to ABCB1 1236/2677/3435 diplotype (n = 9, CGC/CGC; n = 10, CGC/TTT; n = 10, TTT/TTT). In one phase, participants received a single 100 mg dose of sitagliptin; in the other phase, participants received 40 mg of atorvastatin for 5 days, with a single 100 mg dose of sitagliptin administered on day 5. A 24-h pharmacokinetic study followed each sitagliptin dose, and the study phases were separated by a 14-day washout period.
Sitagliptin pharmacokinetic parameters did not differ significantly between ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotype groups during the monotherapy phase. Atorvastatin administration did not significantly affect sitagliptin pharmacokinetics, with geometric mean ratios (90 % confidence intervals) for sitagliptin maximum plasma concentration, plasma concentration–time curve from zero to infinity, renal clearance, and fraction of sitagliptin excreted unchanged in the urine of 0.93 (0.86–1.01), 0.96 (0.91–1.01), 1.02 (0.93–1.12), and 0.98 (0.90–1.06), respectively.
ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes did not influence sitagliptin pharmacokinetics in healthy volunteers. Furthermore, atorvastatin had no effect on the pharmacokinetics of sitagliptin in the setting of ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes.
KeywordsSitagliptin Atorvastatin ABCB1 P-glycoprotein Pharmacogenetics Pharmacokinetics
We would like to thank the study volunteers for their participation, and the nursing and administrative staff at the University of Colorado Clinical and Translational Research Center for assisting with the conduct of the study. The study was funded by National Institutes of Health (NIH) grants R03 DK084089 (to CLA) and UL1 TR000154 (to University of Colorado). The research utilized the services of the Medicinal Chemistry Core facility (MFW) housed within the Department of Pharmaceutical Sciences at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences. The Medicinal Chemistry Core facility receives funding via the Colorado Clinical and Translational Sciences Institute (CCTSI), which is supported in part by CTSA grant UL1TR000154 from NIH/NCRR. The contents of this article are the authors’ sole responsibility and do not necessarily represent official NIH views.
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