Metabolism and pharmacokinetics of a dipeptidyl peptidase IV inhibitor in rats, dogs, and monkeys with selective carbamoyl glucuronidation of the primary amine in dogs.
The pharmacokinetics and metabolism of the l-threo isoleucine thiazolidide dipeptidyl peptidase IV inhibitor, di-[2S,3S]-2-amino-3-methyl-pentanoic-1,3-thiazolidine fumarate (ILT-threo) and its allo stereoisomer (ILT-allo) were evaluated in rats, dogs, and monkeys. Both compounds were well absorbed (>80%) in all species, and most of the dose (>60%) was recovered in urine. Metabolites identified in all species included a sulfoxide (M1), a sulfone (M2), and a carbamoyl glucuronide (M3). For both compounds, parent drug had moderate systemic clearance in rats and dogs ( approximately 20-35 ml/min/kg in both species) and lower clearance in monkeys ( approximately 6-9 ml/min/kg). In rats, M1 was present in systemic circulation in concentrations similar to that of parent drug, whereas in dogs and monkeys, exposures to M1 were higher than for parent drug. In dogs, exposures to the sulfoxide metabolite were approximately 2 to 3 times higher after administration of ILT-allo than after administration of ILT-threo. Carbamoyl glucuronidation was an important biotransformation pathway in dogs. Circulating levels of M3 were significant in the dog, and present only in trace levels in rats and monkeys. M3 could be produced in in vitro systems in a NaHCO3 buffer under a CO2-saturated atmosphere and in the presence of UDP-glucuronic acid and alamethicin.
Beconi
Maria G
MG
Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, .USA maria_beconi@merck.com
Mao
Ann
A
Liu
David Q
DQ
Kochansky
Christopher
C
Pereira
Tony
T
Raab
Conrad
C
Pearson
Paul
P
Lee Chiu
Shuet-Hing
SH
D000588:Amines / Q000378:metabolism*; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004285:Dogs; D020719:Glucuronides / Q000378:metabolism*; D000882:Haplorhini; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D013045:Species Specificity
D000588:Amines; D020719:Glucuronides; D015842:Serine Proteinase Inhibitors; D018819:Dipeptidyl Peptidase 4