Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Abstract

ABSTRACT:Saxagliptin is a potent dipeptidyl peptidase-4 inhibitor approved for the treatment of type 2 diabetes mellitus. The pharmacokinetics and disposition of [ 14 C]saxagliptin were investigated in healthy male subjects after a single 50-mg (91.5 Ci) oral dose. Saxagliptin was rapidly absorbed (T max , 0.5 h). Unchanged saxagliptin and 5-hydroxy saxagliptin (M2), a major, active metabolite, were the prominent drug-related components in the plasma, together accounting for most of the circulating radioactivity. Approximately 97% of the administered radioactivity was recovered in the excreta within 7 days postdose, of which 74.9% was eliminated in the urine and 22.1% was excreted in the feces. The parent compound and M2 represented 24.0 and 44.1%, respectively, of the radioactivity recovered in the urine and feces combined. Taken together, the excretion data suggest that saxagliptin was well absorbed and was subsequently cleared by both urinary excretion and metabolism; the formation of M2 was the major metabolic pathway. Additional minor metabolic pathways included hydroxylation at other positions and glucuronide or sulfate conjugation. Cytochrome P450 (P450) enzymes CYP3A4 and CYP3A5 metabolized saxagliptin and formed M2. Kinetic experiments indicated that the catalytic efficiency (V max /K m ) for CYP3A4 was approximately 4-fold higher than that for CYP3A5. Therefore, it is unlikely that variability in expression levels of CYP3A5 due to genetic polymorphism will impact clearance of saxagliptin. Saxagliptin and M2 each showed little potential to inhibit or induce important P450 enzymes, suggesting that saxagliptin is unlikely to affect the metabolic clearance of coadministered drugs that are substrates for these enzymes.

CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48

“…These include saxagliptin and vildagliptin, two dipeptidyl peptidase-4 (DPP-4) inhibitors used as hypoglycemic agents in the treatment of type 2 diabetes mellitus (30). The primary pathway for biotransformation of saxagliptin in humans involves CYP3A4/5-dependent monohydroxylation on the 3-hydroxy-substituted adamantyl moiety to form a 5-hydroxy saxagliptin metabolite (31). The metabolism of vildagliptin, on the other hand, is virtually CYPindependent and predominantly involves hydrolysis at other parts of the molecule likely attributable to the DPP-4 target enzyme itself (32), which could explain the lack of CYP involvement.…”

Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor

“…Renal clearance contributed to the overall elimination of both saxagliptin and 5-hydroxy saxagliptin. The metabolism of saxagliptin is primarily mediated by CYP3A4/5 (CYP3A) [26]. In in vitro studies, saxagliptin and 5-hydroxy saxagliptin did not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4, and did not induce CYP1A2, 2B6, 2C9 or 3A4 [7,26].…”

“…The metabolism of saxagliptin is primarily mediated by CYP3A4/5 (CYP3A) [26]. In in vitro studies, saxagliptin and 5-hydroxy saxagliptin did not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4, and did not induce CYP1A2, 2B6, 2C9 or 3A4 [7,26]. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes.…”

“…Saxagliptin is primarily metabolized by CYP3A4/3A5; data from a study administering radiolabelled saxagliptin indicated that 5-hydroxy saxagliptin is the major metabolite of saxagliptin in humans [26]. The parent-to-metabolite ratio generally remained constant within individual subjects upon multiple dosing or when determined on different occasions, indicating that saxagliptin does not induce its own metabolic clearance [15].…”

“…Saxagliptin has high aqueous solubility ([17 ng/mL) relative to its usual dose of up to 5 mg. Although its in vitro permeability was indicative of poor absorption in a Caco-2 transcellular permeability assay [ [25] unpublished data 2007], the absolute oral bioavailability and recovery of total radioactivity (TRA) in human and animal urine indicated extensive oral absorption (50-75 % absorption) [25][26][27].…”