| In vitro and in vivo evaluation of a novel water-soluble N-glycyl prodrug (N-GLY-CBZ) of carbamazepine. | |
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MedLine Citation:
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PMID: 20845455 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The synthesis and characterization of N-glycyl-carbamazepine (N-Gly-CBZ), an N-acyl urea derivative of carbamazepine (CBZ) designed to act as a prodrug and convert to CBZ and glycine in vivo by enzymatic cleavage of the glycyl-urea bond was recently reported. The rate and extent of conversion of N-Gly-CBZ to CBZ in a whole animal model is reported here along with supporting in vitro data. Pharmacokinetic parameters were determined for N-Gly-CBZ and CBZ following IV and oral administration of N-Gly-CBZ and CBZ control to rats using a crossover design. The in vivo elimination of N-Gly-CBZ following IV administration in rats was biphasic in nature with a t(1/2) of about 1.1 min, which was very similar to the t(1/2) for appearance of CBZ. The mean value for the relative AUC ratio for CBZ from N-Gly-CBZ and CBZ from a cyclodextrin solution showed that N-Gly-CBZ delivered a (± SD) 98 ± 16% (± SD) equivalent dose of CBZ in six rats. The results of the IV dosing pharmacokinetics investigation were consistent with N-Gly-CBZ acting as a prodrug with rapid and complete conversion to CBZ in vivo. The overall absolute oral bioavailability of CBZ from N-Gly-CBZ was determined to be 41 ± 14% in three rats. The relative oral bioavailability of CBZ from N-Gly-CBZ compared to an oral CBZ control was 1.72 ± 0.54. That is, the prodrug, N-Gly-CBZ, demonstrated superior oral bioavailability of CBZ over the CBZ control, which was likely due to its greater aqueous solubility. |
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Authors:
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Jeffrey N Hemenway; Valentino J Stella |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of pharmaceutical sciences Volume: 99 ISSN: 1520-6017 ISO Abbreviation: J Pharm Sci Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-09-16 Completed Date: 2011-01-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985195R Medline TA: J Pharm Sci Country: United States |
Other Details:
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Languages: eng Pagination: 4565-75 Citation Subset: IM |
Copyright Information:
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© 2010 Wiley-Liss, Inc. and the American Pharmacists Association |
Affiliation:
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Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Analgesics, Non-Narcotic / chemistry, metabolism*, pharmacokinetics* Animals Carbamazepine / analogs & derivatives, metabolism*, pharmacokinetics* Drug Stability Male Prodrugs / chemistry, metabolism*, pharmacokinetics* Rats Rats, Sprague-Dawley Solubility Water / chemistry |
| Chemical | |
Reg. No./Substance:
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0/Analgesics, Non-Narcotic; 0/Prodrugs; 298-46-4/Carbamazepine; 7732-18-5/Water |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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