| Abstrakt: |
The pharmacokinetics and metabolism of 2,2,3,3-tetramethylcyclopropanecarbonylurea (TMCU), a potent anticonvulsant compound, were studied in male Sprague-Dawley rats following i.v. (5 mg/kg), oral (20 mg/kg), and i.p. (20 mg/kg) administrations. Urine samples were analyzed by gas chromatography-mass spectrometry (GC/MS) and liquid chromatography-mass spectrometry. Plasma samples were analyzed by GC/MS. TMCU absolute bioavailability was 83% and 90% following oral and i.p. dosing, respectively. Following i.p. administration, the peak plasma concentration (Cmax) obtained 45 min after dosing was 15.4 mg/l. Following oral dosing, Cmax was 6.5 mg/l, and it was reached after 4 h. The disposition kinetics of TMCU in rats was adequately described by a one-compartment open body model. TMCU is well distributed into the extravascular tissues with volume of distribution (Vss) of 0.87 l/kg and undergoes extensive metabolism. Only a small fraction of TMCU excreted unmetabolized in the urine (6.3 ± 0.8%). trans-2-Hydroxymethyl-2,3,3-trimethylcyclopropanecarbonylurea (OH-TMCU) was a predominant metabolite of TMCU. Its structure was established by NMR and X-ray crystallography. Following i.p. administration of 5 and 20 mg/kg TMCU, the drug was excreted in the urine as OH-TMCU at an extent of 28.3 ± 2.6% and 42.1 ± 3.8%, respectively. A portion of OH-TMCU was excreted in the urine as TMCU sulfate and TMCU glucuronide. |
