Metabolism, excretion, and pharmacokinetics of ((3,3-difluoropyrrolidin-1-yl)((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, a dipeptidyl peptidase inhibitor, in rat, dog and human.
The disposition of 3,3-difluoropyrrolidin-1-yl{(2S,4S)-4-[4-(pyrimidin-2-yl)piperazin-1-yl]pyrrolidin-2-yl}methanone (PF-00734200), a dipeptidyl peptidase IV inhibitor that progressed to phase 3 for the treatment of type 2 diabetes, was examined in rats, dogs, and humans after oral administration of a single dose of [(14)C]PF-00734200. Mean recoveries of administered radioactivity were 97.1, 92.2, and 87.2% in rats, dogs, and humans, respectively. The majority of radioactive dose was detected in the urine of dogs and humans and in the feces of rats. Absorption of PF-00734200 was rapid in all species, with maximal plasma concentrations of radioactivity achieved within 1 h after the dose. Circulating radioactivity was primarily composed of the parent drug (79.9, 80.2, and 94.4% in rat, dog, and human, respectively). The major route of metabolism was due to hydroxylation at the 5' position of the pyrimidine ring (M5) in all species. In vitro experiments with recombinant cytochrome P450 isoforms suggested that the formation of M5 was catalyzed both by CYP2D6 and CYP3A4. Molecular docking simulations showed that the 5' position of the pyrimidine moiety of PF-00734200 can access the heme iron-oxo of both CYP3A4 and CYP2D6 in an energetically favored orientation. Other metabolic pathways included amide hydrolysis (M2), N-dealkylation at the piperazine nitrogen (M3) and an unusual metabolite resulting from scission of the pyrimidine ring (M1). Phase II metabolic pathways included the following: carbamoyl glucuronidation (M9), glucosidation (M15) on the pyrrolidine nitrogen, and conjugation with creatinine to form an unusual metabolite/metabonate (M16). The data from these studies suggest that PF-00734200 is eliminated by both metabolism and renal clearance.
Departments of Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA.
Raman
R
Sharma
Hao
H
Sun
David W
DW
Piotrowski
Tim F
TF
Ryder
Shawn D
SD
Doran
Haiqing
H
Dai
Chandra
C
Prakash
D000577:Amides / Q000378:metabolism; D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000652:urine; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D050217:Metabolic Detoxication, Phase II; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation / Q000379:methods; D000077489:Piperazine; D010879:Piperazines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism* / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D000577:Amides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D011759:Pyrrolidines; D000077489:Piperazine; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C558848:gosogliptin; C030986:pyrimidine; C032519:pyrrolidine