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First published on July 21, 2005; DOI: 10.1124/dmd.105.005637

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Received for publication May 23, 2005.
Revised July 20, 2005.
Accepted for publication July 20, 2005.

PHARMACOKINETICS AND METABOLISM OF A NEW POTENT ANTIEPILEPTIC DRUG, 2,2,3,3-TETRAMETHYCYCLOPROPANECARBONYLUREA, IN RATS

Eyal Sobol 1, Boris Yagen 2, Ilan Winkler 3, Malka Britzi 4, Dan Gibson 5, Meir Bialer 1*

1 Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Israel 2 Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Hebrew University, 3 Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem,Israel 4 National Residue Control Laboratory, Kimron Veterinary Institute, Beit Dagan, Israel 5 Department of Medicinal Chemistry and Natural Products , School of Pharmacy, Hebrew Univeristy.

* Address correspondence to: E-mail: bialer{at}md.huji.ac.il

Abstract

The pharmacokinetics and metabolism of 2,2,3,3-tetramethylcyclopropanecarbonylurea (TMCU), a potent anticonvulsant compound, were studied in male Sprague-Dawley rats following intravenous (i.v., 5 mg/kg), oral (20 mg/kg) and intraperitoneal (i.p., 20 mg/kg) administrations. Urine samples were analyzed by GC/MS and LC/MS. 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 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.


Key words: CNS pharmacokinetics, drug design, drug development, drug discovery, drug disposition, metabolite identification, metabolite kinetics, pharmacokinetics




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