title: Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Merck Research Laboratories, Merck & Co, Inc, 126 East Lincoln Avenue, Rahway, NJ 07065, USA. rajesh_krishna@merck.com.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
authors.forename: Arthur
authors.initials: A
authors.lastname: Bergman
authors.forename: Patrick
authors.initials: P
authors.lastname: Larson
authors.forename: Josee
authors.initials: J
authors.lastname: Cote
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lasseter
authors.forename: Stacey
authors.initials: S
authors.lastname: Dilzer
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zeng
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Wagner
authors.forename: Gary
authors.initials: G
authors.lastname: Herman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D058892:Adenosine Deaminase Inhibitors; D000328:Adult; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004347:Drug Interactions; D006023:Glycoproteins / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D008297:Male; D011719:Pyrazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D058892:Adenosine Deaminase Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D011719:Pyrazines; D014230:Triazoles; D016572:Cyclosporine; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate