DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on July 21, 2005; DOI: 10.1124/dmd.105.005637

0090-9556/05/3310-1538-1546$20.00
DMD 33:1538-1546, 2005

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.105.005637v1
33/10/1538    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sobol, E.
Right arrow Articles by Bialer, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sobol, E.
Right arrow Articles by Bialer, M.

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

Eyal Sobol, Boris Yagen, Ilan Winkler, Malka Britzi, Dan Gibson, and Meir Bialer

Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, the Hebrew University of Jerusalem, Jerusalem, Israel (E.S., I.W., M.B., M.Bi.); Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, the Hebrew University of Jerusalem, Jerusalem, Israel (B.Y., D.G.); National Residue Control Laboratory, Kimron Veterinary Institute, Beit Dagan, Israel (M.B.); and the David R. Bloom Center for Pharmacy, the Hebrew University of Jerusalem, Jerusalem, Israel (B.Y., D.G., M.Bi)

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.

Address correspondence to: Professor Meir Bialer, Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O.B. 12065 Ein Karem, Jerusalem 91120, Israel. E-mail: bialer{at}md.huji.ac.il






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2005 by the American Society for Pharmacology and Experimental Therapeutics.