Document Detail

Zidovudine and Ursodeoxycholic Acid Conjugation: Design of a New Prodrug Potentially Able to Bypass the Active Efflux Transport Systems of the Central Nervous System.
MedLine Citation:
PMID:  22356133     Owner:  NLM     Status:  Publisher    
We have synthesized a new prodrug obtained by the 5'-ester-conjugation of zidovudine (AZT), an antiviral agent substrate of active efflux transport systems (AET), with ursodeoxycholic acid (UDCA), a bile acid able to permeate into the central nervous system (CNS). We have demonstrated, by HPLC analysis, that UDCA-AZT is quickly hydrolyzed in rat plasma and whole blood (half life < 10 seconds). The same compound was hydrolyzed with slower rates in human plasma (half-life = 7.53±0.44 hours) and whole blood (half-life = 3.71±0.16 hours), allowing to control the AZT release. UDCA-AZT appeared hydrolyzed also in rat brain (half-life = 7.24±0.45 minutes) and liver homogenates (half-life = 2.70 ±0.14 minutes). In the aim to study the permeation properties of the UDCA-AZT across physiological barriers, we have used an established human retinal pigment epithelium (HRPE) cell line to obtain a polarized cell monolayer showing epithelial features. The bidirectional permeation of 30 µM AZT across this monolayer was regulated by apparent permeability coefficients (PE) higher from the apical to basolateral compartments (PE = 209±4 x 10-5 cm/min) than in the opposite way (PE = 133±8 x 10-5 cm/min), in conformity with the in vivo behavior of AZT, actively effluxed from the CNS. The influx (PE = 39.1±1.2 x 10-5 cm/min) and efflux (PE = 31.3±3.6 x 10-5 cm/min) permeability coefficients of 30 µM UDCA-AZT were instead the same, suggesting the ability of the prodrug to avoid the AET systems and, potentially, to allow its accumulation in the CNS. The relatively low PE values of UDCA-AZT were associated to a partial hydrolysis during its permeation across the cell monolayer.
Alessandro Dalpiaz; Guglielmo Paganetto; Barbara Pavan; Marco Fogagnolo; Alessandro Medici; Sarah Beggiato; Daniela Perrone
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-2-22
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  -     ISSN:  1543-8392     ISO Abbreviation:  -     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-2-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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