RT Journal Article
SR Electronic
T1 Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1345
OP 1356
DO 10.1124/dmd.112.045450
VO 40
IS 7
A1 Hong Su
A1 David W. Boulton
A1 Anthony Barros, Jr.
A1 Lifei Wang
A1 Kai Cao
A1 Samuel J. Bonacorsi, Jr.
A1 Ramaswamy A. Iyer
A1 W. Griffith Humphreys
A1 Lisa J. Christopher
YR 2012
UL http://dmd.aspetjournals.org/content/40/7/1345.abstract
AB Saxagliptin is a potent dipeptidyl peptidase-4 inhibitor approved for the treatment of type 2 diabetes mellitus. The pharmacokinetics and disposition of [14C]saxagliptin were investigated in healthy male subjects after a single 50-mg (91.5 μCi) oral dose. Saxagliptin was rapidly absorbed (Tmax, 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 (Vmax/Km) 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.