Disposition of the Dipeptidyl Peptidase 4 Inhibitor Sitagliptin in Rats and Dogs

Abstract

ABSTRACT:The pharmacokinetics, metabolism, and excretion of sitagliptin The plasma clearance and volume of distribution of sitagliptin were higher in rats (40-48 ml/min/kg, 7-9 l/kg) than in dogs (ϳ9 ml/min/kg, ϳ3 l/kg), and its half-life was shorter in rats, ϳ2 h compared with ϳ4 h in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. After administration of [ 14 C]sitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile, and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, whereas metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32 to 39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.Dipeptidyl peptidase 4 (DPP-4) is a ubiquitous proline-specific serine protease responsible for the rapid inactivation of the incretin glucagon-like peptide 1 (GLP-1) (Mentlein et al., 1993;Gorrell, 2005). GLP-1 and GLP-1 analogs have been shown to decrease fasting and postprandial glucose in diabetic patients when given as a continuous intravenous infusion or by subcutaneous administration (Zander et al., 2002;Gautier et al., 2005). The effectiveness of orally administered DPP-4 inhibitors has been demonstrated in obese Zucker rats (Balkan et al., 1999;Pospisilik et al., 2002), mice (Mu et al., 2006, and humans (Ahren et al., 2004;Herman et al., 2004Herman et al., , 2005aScott et al., 2005;Cornell, 2006). Thus, stabilization of GLP-1 via DPP-4 inhibition represents a new therapeutic approach for type 2 diabetes (Drucker, 2006;Green et al., 2006).Sitagliptin ( (Fig. 1), is a potent and selective, reversible inhibitor of DPP-4 with an IC 50 value of 18 nM (Kim et al., 2005). Sitagliptin has been shown to inhibit plasma DPP-4 activity in normal volunteers (Herman et al., 2005a;Bergman et al., 2006) and in patients with type 2 diabetes (Herman et al., 2004), and to significantly reduce HbA 1c and fasting plasma glucose in patients with type 2 diabetes (Herman et al., 2005b;Scott et al., 2005). In support of the suitability of the rat and dog as toxicology species, the disposition of sitagliptin was evaluated in these species and compared with that in humans. Results from in vitro (rat, dog, human) and in vivo studies in rats and dogs are discussed herein. The absorption, metabolism, and excretion of sitagliptin in humans are reported in the accompanying article . Materials and MethodsChemicals and Reagents. Sitagliptin was prep...

Metabolism And Excretion of the Dipeptidyl Peptidase 4 Inhibitor [14C]Sitagliptin in Humans

“…Similar observations were made in rats and dogs (Beconi et al, 2007), where, as in humans, sitagliptin was eliminated primarily unchanged into urine (dog) or urine and bile (rat). Also, all the metabolites observed in human plasma, urine, and feces were observed also in rat and/or dog plasma, urine, bile, and feces, as well as in incubations in vitro with rat, dog, and human liver preparations (Beconi et al, 2007).…”

“…Also, all the metabolites observed in human plasma, urine, and feces were observed also in rat and/or dog plasma, urine, bile, and feces, as well as in incubations in vitro with rat, dog, and human liver preparations (Beconi et al, 2007). Results from in vitro experiments with recombinant P450s and monoclonal anti-P450 antibodies indicated that the oxidative metabolism of sitagliptin in human liver microsomes is catalyzed primarily by CYP3A4 with some minor contribution from CYP2C8.…”

“…The only metabolites detected by LC-MS/MS were a hydroxylated derivative (M6), and the cyclized products M2 and M5 (Beconi et al, 2007). Incubations with recombinant P450s indicated that CYP3A4 and, to a much smaller extent, CYP2C8 were capable of catalyzing the formation of M2, M5, and M6.…”

“…In preclinical species, [ 14 C]sitagliptin was shown to be eliminated by biliary and/or renal excretion of parent drug (Beconi et al, 2007). Metabolism was minimal, and it involved N-sulfation (M1), N-carbamoyl glucuronidation (M4), hydroxylation (M6) followed by ether glucuronidation (M3), and oxidative desaturation followed by cyclization (M2 and M5) (Fig.…”

Characterization of Two Cyclic Metabolites of Sitagliptin

“…Sitagliptin has been shown to inhibit plasma DPP-4 activity in normal volunteers (Bergman et al, 2005(Bergman et al, , 2006Herman et al, 2005a) and patients with type 2 diabetes (Herman et al, 2004), and to significantly reduce HbA 1c and fasting plasma glucose in patients with type 2 diabetes (Herman et al, 2005b;Scott et al, 2005). The pharmacokinetics, metabolism, and excretion of sitagliptin in rats, dogs, and humans are described elsewhere (Beconi et al, 2007;Bergman et al, 2006;Vincent et al, 2007). The objective of the present studies was to characterize two metabolites of sitagliptin, referred to as M2 and M5.…”