Document Detail


In vitro and in vivo evaluation of a novel water-soluble N-glycyl prodrug (N-GLY-CBZ) of carbamazepine.
MedLine Citation:
PMID:  20845455     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jeffrey N Hemenway; Valentino J Stella
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  99     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-09-16     Completed Date:  2011-01-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4565-75     Citation Subset:  IM    
Copyright Information:
© 2010 Wiley-Liss, Inc. and the American Pharmacists Association
Affiliation:
Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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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