title: Pharmacokinetics and metabolism of the dipeptidyl peptidase IV inhibitor carmegliptin in rats, dogs, and monkeys.
abstract: The pharmacokinetics and excretion of carmegliptin, a novel dipeptidyl peptidase IV inhibitor, were examined in rats, dogs, and cynomolgus monkeys. Carmegliptin exhibited a moderate clearance, extensive tissue distribution, and a variable oral bioavailability of 28-174%. Due to saturation of intestinal active secretion, the area under the plasma concentration-time curve (AUC) in dogs and monkeys increased in a more than dose-proportional manner over an oral dose range of 2.5-10 mg/kg. Following oral administration of [(14)C]carmegliptin at 3 mg/kg, > 94% of the radioactive dose was recovered in 72-h post-dose from Wistar rats and Beagle dogs. Virtually, the entire administered radioactive dose was excreted unchanged in urine, intestinal lumen, and bile. Approximately 36%, 29%, and 19% of the dose were excreted by respective routes. Consistently, in vitro, carmegliptin was highly resistant to hepatic metabolism in all species tested. Based on in vitro studies, carmegliptin is a good substrate for Mdr1/MDR1. Breast cancer resistance protein (Bcrp) is not expected to be involved in the transport of carmegliptin since in vitro carmegliptin was not significantly transported by this transporter. The very high extravascular distribution of carmegliptin in the intestinal tissues, as demonstrated in Wistar rats and Beagle dogs, could play a significant role in its therapeutic effect.
authors.affiliation: Non-Clinical Drug Safety, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland. olaf.kuhlmann@roche.com
authors.forename: Olaf
authors.initials: O
authors.lastname: Kuhlmann
authors.forename: Axel
authors.initials: A
authors.lastname: Paehler
authors.forename: Idelette
authors.initials: I
authors.lastname: Weick
authors.forename: Christoph
authors.initials: C
authors.lastname: Funk
authors.forename: Michael
authors.initials: M
authors.lastname: Pantze
authors.forename: Manfred
authors.initials: M
authors.lastname: Zell
authors.forename: Uwe
authors.initials: U
authors.lastname: Timm
mesh_terms: D000042:Absorption; D000818:Animals; D001345:Autoradiography; D001682:Biological Availability; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D000882:Haplorhini; D007275:Injections, Intravenous; D026901:Membrane Transport Proteins / Q000378:metabolism; D011807:Quinolizines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D001798:Blood Proteins; D054873:Dipeptidyl-Peptidase IV Inhibitors; D026901:Membrane Transport Proteins; D011807:Quinolizines; C552198:carmegliptin