Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects

J Clin Pharmacol. 2007 Feb;47(2):165-74. doi: 10.1177/0091270006296523.


Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C(24 h), suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Adenosine Deaminase Inhibitors
  • Adult
  • Cross-Over Studies
  • Cyclosporine / adverse effects
  • Cyclosporine / pharmacology*
  • Dipeptidyl Peptidase 4
  • Dipeptidyl-Peptidase IV Inhibitors
  • Drug Interactions
  • Glycoproteins / antagonists & inhibitors
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics
  • Kidney / metabolism
  • Male
  • Pyrazines / adverse effects
  • Pyrazines / blood
  • Pyrazines / pharmacokinetics*
  • Sitagliptin Phosphate
  • Triazoles / adverse effects
  • Triazoles / blood
  • Triazoles / pharmacokinetics*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Adenosine Deaminase Inhibitors
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycoproteins
  • Hypoglycemic Agents
  • Pyrazines
  • Triazoles
  • Cyclosporine
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Sitagliptin Phosphate