Document Detail

Synthesis and in vitro evaluation of gabapentin prodrugs that target the human apical sodium-dependent bile acid transporter (hASBT).
MedLine Citation:
PMID:  20848648     Owner:  NLM     Status:  MEDLINE    
Gabapentin is a zwitterionic drug that exhibits low and variable oral absorption at therapeutic doses. The human apical sodium-dependent bile acid transporter (hASBT; SLC10A2) is a potential prodrug target to increase oral drug absorption. The objective was to evaluate several bile acid conjugates of gabapentin as potential prodrugs that target hASBT. Five analogues were synthesized and varied in ionic nature and the presence or absence of glutamic acid linker between the bile acid and drug. Analogues were evaluated for their inhibition and uptake properties using stably transfected hASBT-MDCK cells. The two monoanionic conjugates were potent hASBT substrates, with high affinity (K(m) of 16.3 and 5.99 μM) and high capacity (V(max) of 0.656 and 0.842 pmol/cm(2) /s). The dianionic conjugate inhibited hASBT with moderate potency but was not a substrate. The two monoanionic conjugates were catalytically degraded in Caco-2 homogenate and rat liver microsomes. Each yielded gabapentin from prodrug. These two conjugates are novel prodrugs of gabapentin and illustrate prodrugs that can be designed to target hASBT.
Rana Rais; Steven Fletcher; James E Polli
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-09-16
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  100     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-01-31     Completed Date:  2011-08-17     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1184-95     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Wiley-Liss, Inc.
Univerisity of Maryland School of Pharmacy, Baltimore, Maryland 21201, USA.
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MeSH Terms
Amines / administration & dosage,  chemistry,  pharmacokinetics
Anticonvulsants / administration & dosage,  chemistry,  pharmacokinetics,  pharmacology*
Bile Acids and Salts / chemistry,  metabolism*
Biological Transport
Caco-2 Cells
Cell Line
Chenodeoxycholic Acid / chemistry,  metabolism
Cyclohexanecarboxylic Acids / administration & dosage,  chemistry,  pharmacokinetics
Drug Stability
Glutamic Acid / metabolism
Microsomes, Liver / metabolism
Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors*,  metabolism*
Prodrugs / administration & dosage,  chemical synthesis*,  pharmacokinetics,  pharmacology*
Symporters / antagonists & inhibitors*,  metabolism*
gamma-Aminobutyric Acid / administration & dosage,  chemistry,  pharmacokinetics
Grant Support
Reg. No./Substance:
0/Amines; 0/Anticonvulsants; 0/Bile Acids and Salts; 0/Cyclohexanecarboxylic Acids; 0/Organic Anion Transporters, Sodium-Dependent; 0/Prodrugs; 0/Symporters; 145420-23-1/sodium-bile acid cotransporter; 474-25-9/Chenodeoxycholic Acid; 56-12-2/gamma-Aminobutyric Acid; 56-86-0/Glutamic Acid; 6CW7F3G59X/gabapentin

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