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 (K m ϭ 162 M), 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 (IC 50 ϭ 160 M). hOAT3-mediated sitagliptin uptake was inhibited by probenecid, ibuprofen, furosemide, fenofibric acid, quinapril, indapamide, and cimetidine with IC 50 values of 5.6, 3.7, 1.7, 2.2, 6.2, 11, and 79 M, respectively. Sitagliptin did not inhibit Pgp-mediated transport of digoxin, verapamil, ritonavir, quinidine, and vinblastine. Cyclosporine A significantly inhibited Pgp-mediated transport of sitagliptin (IC 50 ϭ 1 M). 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.Sitagliptin [also known as MK-0431 ( Fig. 1)], is a selective, reversible inhibitor of dipeptidyl-peptidase 4 recently approved by the Food and Drug Administration for the treatment of type 2 diabetes (Deacon, 2005;Kim et al., 2005). Dipeptidyl-peptidase 4 inhibitors have a glucose-lowering effect by inhibiting the inactivation of incretin peptides, including glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are released upon nutrient ingestion, stimulate meal-induced insulin secretion, and contribute to glucose homeostasis (Kieffer and Habener, 1999). The pharmacokinetics, metabolism, and excretion of sitagliptin have been investigated in humans and animals Herman et al., 2005Herman et al., , 2006Beconi et al., 2007). After a single oral dose of sitagliptin (1.5-600 mg) in healthy male volunteers, sitagliptin was well absorbed with an apparent terminal half-life ranging from 8 to 14 h. Sitagliptin was primarily renally eliminated as unchanged drug (Herman et al., 2005), with metabolism playing only a minor role (Vincent et al., 2007). Renal clearance of sitagliptin averaged approximately 388 ml/min in humans (Herman et al., 2005). Given that sitagliptin is approximately Article, publication date, and citation information can be found at

Digoxin Is Not a Substrate for Organic Anion-Transporting Polypeptide Transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but Is a Substrate for a Sodium-Dependent Transporter Expressed in HEK293 Cells

“…Expression of Endogenous Transporter Genes (mRNA) in HEK293 Cells. Because digoxin and ouabain have been reported as substrates of OATP4C1 (Mikkaichi et al, 2004;Chu et al, 2007), analysis of the HEK293 cell line using a gene chip was conducted at Pfizer to determine if genes for any known human uptake and efflux membrane transporters are endogenously expressed that may contribute to the active transport of digoxin or ouabain in these cells (Table 3). Among the known transporters identified in this analysis, the monocarboxylic acid transporter-1 gene was the membrane transporter gene demonstrating the highest expression levels with a value of 4028 MAS5 units, which is approximately one-sixth of the level of the most abundant gene (ribosomal protein L13 of ϳ30,000).…”

“…Most clinical investigations conducted to date have focused on P-gpmediated drug interactions [e.g., DDI studies involving digoxin and amiodarone (Robinson et al, 1989) and quinidine (Rameis, 1985)]. However, two publications suggest that, in addition to P-gp, digoxin is also a substrate for OATP1B3 (Kullak-Ublick et al, 2001) and OATP4C1 (Mikkaichi et al, 2004;Chu et al, 2007). The consequences of a coadministered medication inhibiting the uptake of digoxin into the liver or kidney by inhibiting OATP1B3 or OATP4C1, respectively, could also theoretically result in elevated digoxin exposures that may be indistinguishable from an effect caused by inhibition of P-gp.…”

“…In rats, digoxin was reported to be a substrate for Oatp2 and Oatp4 (Cattori et al, 2000;Funakoshi et al, 2005). Digoxin has also been reported to be a substrate for human liver OATP1B3 (Kullak-Ublick et al, 2001) and kidney OATP4C1 (Mikkaichi et al, 2004;Chu et al, 2007) on the basis of studies conducted using recombinant expression systems. Thus, if DDIs involving digoxin administration could also occur upon coadministration with drugs that inhibit OATPs, this may be an additional cause for concern.…”

Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure

“…Of the rosuvastatin disposition pathways, OAT3 inhibition is unlikely to contribute to these DDIs because darunavir and fluconazole do not inhibit OAT3 in vitro, and eltrombopag (K i = 7.8 mM), lopinavir (K i . 10 mM), and fenofibric acid (K i = 2.2 mM) are not predicted to inhibit OAT3 in vivo based on C max u /K i ratios being ,0.1 (Chu et al, 2007;Yoshida et al, 2012). Additionally, inhibition of OATP1B3 is unlikely to play a role since, although eltrombopag (K i = 25.6 mM), darunavir (K i = 4.51 mM), and ezetimibe (K i .…”

Pharmacokinetic evaluation of atorvastatin and sitagliptin in combination for the treatment of type 2 diabetes

“…Sitagliptin is transported by hOAT3, organic anion transporting polypeptide OATP4C1 and multidrug resistance (MDR) Pgp. In vitro studies suggested that hOAT3, OATP4C1 and MDR1 Pgp might play a role in transporting sitagliptin into and out of renal proximal tubule cells, respectively [36]. However, experimental in vitro data indicated that sitagliptin is unlikely to be a perpetrator of DDIs with Pgp, hOATl or hOAT3 substrates at clinically relevant concentrations and no in vivo clinically meaningful interactions have been described yet [20].…”