title: Pharmacokinetics and metabolism of a new potent antiepileptic drug, 2,2,3,3-tetramethycyclopropanecarbonylurea, in rats.
abstract: 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 (C(max)) obtained 45 min after dosing was 15.4 mg/l. Following oral dosing, C(max) 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 (V(ss)) 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O.B. 12065 Ein Karem, Jerusalem 91120, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Sobol
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.forename: Ilan
authors.initials: I
authors.lastname: Winkler
authors.forename: Malka
authors.initials: M
authors.lastname: Britzi
authors.forename: Dan
authors.initials: D
authors.lastname: Gibson
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation; D003521:Cyclopropanes / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C488794:2,2,3,3-tetramethylcyclopropanecarbonylurea; D000927:Anticonvulsants; D003521:Cyclopropanes; D014508:Urea