| Synthesis and in vitro evaluation of gabapentin prodrugs that target the human apical sodium-dependent bile acid transporter (hASBT). | |
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MedLine Citation:
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PMID: 20848648 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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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. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1184-1195, 2011. |
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Authors:
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Rana Rais; Steven Fletcher; James E Polli |
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Publication Detail:
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Type: Journal Article Date: 2010-09-16 |
Journal Detail:
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Title: Journal of pharmaceutical sciences Volume: 100 ISSN: 1520-6017 ISO Abbreviation: J Pharm Sci Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-01-31 Completed Date: - 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: 1184-95 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Wiley-Liss, Inc. |
Affiliation:
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Univerisity of Maryland School of Pharmacy, Baltimore, Maryland 21201. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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