title: Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein.
abstract: Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor recently approved for the treatment of type 2 diabetes, is excreted into the urine via active tubular secretion and glomerular filtration in humans. In this report, we demonstrate that sitagliptin is transported by human organic anion transporter hOAT3 (Km=162 microM), organic anion transporting polypeptide OATP4C1, and multidrug resistance (MDR) P-glycoprotein (Pgp), but not by human organic cation transporter 2 hOCT2, hOAT1, oligopeptide transporter hPEPT1, OATP2B1, and the multidrug resistance proteins MRP2 and MRP4. Our studies suggested that hOAT3, OATP4C1, and MDR1 Pgp might play a role in transporting sitagliptin into and out of renal proximal tubule cells, respectively. Sitagliptin did not inhibit hOAT1-mediated cidofovir uptake, but it showed weak inhibition of hOAT3-mediated cimetidine uptake (IC50=160 microM). hOAT3-mediated sitagliptin uptake was inhibited by probenecid, ibuprofen, furosemide, fenofibric acid, quinapril, indapamide, and cimetidine with IC50 values of 5.6, 3.7, 1.7, 2.2, 6.2, 11, and 79 microM, respectively. Sitagliptin did not inhibit Pgp-mediated transport of digoxin, verapamil, ritonavir, quinidine, and vinblastine. Cyclosporine A significantly inhibited Pgp-mediated transport of sitagliptin (IC50=1 microM). Our data indicate that sitagliptin is unlikely to be a perpetrator of drug-drug interactions with Pgp, hOAT1, or hOAT3 substrates at clinically relevant concentrations. Renal secretion of sitagliptin could be inhibited if coadministered with OAT3 inhibitors such as probenecid. However, the magnitude of interactions should be low, and the effects may not be clinically meaningful, due to the high safety margin of sitagliptin.
authors.affiliation: Department of Drug Metabolism, Merck & Co., RY80-141, 126 East Lincoln Ave., Rahway, NJ 07065, USA. xiaoyan_chu@merck.com
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Chu
authors.forename: Kelly
authors.initials: K
authors.lastname: Bleasby
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Yabut
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Cai
authors.forename: Grace Hoyee
authors.initials: GH
authors.lastname: Chan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hafey
authors.forename: Shiyao
authors.initials: S
authors.lastname: Xu
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Bergman
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Braun
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Dean
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000502:physiology; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology; D027361:Organic Anion Transporters / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology*; D011719:Pyrazines / Q000378:metabolism*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D058892:Adenosine Deaminase Inhibitors; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D014230:Triazoles; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C484530:SLCO4C1 protein, human; C114338:organic anion transport protein 3; C042807:DPP4 protein, human