Abstract
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 (∼20–35 ml/min/kg in both species) and lower clearance in monkeys (∼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 ∼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.
Footnotes
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↵1 Abbreviations used are: GLP-1, glucagon-like peptide 1; DP-IV, dipeptidyl peptidase IV; ILT-threo, di-[2S,3S]-2-amino-3-methyl-pentanoic-1,3-thiazolidine fumarate; ILT-allo, the allo stereoisomer of ILT-threo; IS, internal standard; MRL, Merck Research Laboratories; 5-DPT, 10-[(N,N-dimethylamino)-alkyl]-2-(trifluoromethyl)phenothiazine; UDPGA, UDP-glucuronic acid; HPLC, high performance liquid chromatography; P450, cytochrome P450; FMO, flavin-containing monooxygenase; LC-MS/MS, liquid chromatography-tandem mass spectrometry; AUC, area under the plasma concentration versus time curve; Cl, clearance; Ro 40–5967, mibefradil.
- Received May 27, 2003.
- Accepted July 11, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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