Document Detail

Transport of levovirin prodrugs in the human intestinal Caco-2 cell line.
MedLine Citation:
PMID:  16634069     Owner:  NLM     Status:  MEDLINE    
The transport of 10 amino acid ester prodrugs of levovirin (LVV) was investigated in the human intestinal Caco-2 cell line in order to overcome the poor oral bioavailability of LVV, an investigational drug for the treatment of hepatitis C infection. The prodrugs were designed to improve the permeability of LVV across the intestinal epithelium by targeting the di/tri-peptide carrier, PepT1. Caco-2 cell monolayers were employed to study the transport and hydrolysis properties of the prodrugs. Among all mono amino acid ester prodrugs studied, the LVV-5'-(L)-valine prodrug (R1518) exhibited the maximum increase (48-fold) in permeability with nearly complete conversion to LVV within 1 h. Di-amino acid esters did not offer significant enhancement in permeability comparing with mono amino acid esters and exhibited slower conversion to LVV in Caco2 cell monolayers. Pharmacokinetic screening studies of the prodrugs in rats yielded the highest fold increase (6.9-fold) of AUC with R1518 and in general displayed a similar trend to that observed in increases of permeability in Caco-2 cells. Mechanisms involved in the Caco-2 cell transport of R1518 were also investigated. Results of bi-directional transport studies support the involvement of carrier-mediated transport mechanisms for R1518, but not for the LVV-5'-(D)-valine prodrug or LVV. Moreover, the permeability of R1518 was found to be proton dependent. PepT1-mediated transport of R1518 was supported by results of competitive transport studies of R1518 with the PepT1 substrates enalapril, Gly-Sar, valganciclovir, and cephalexin. R1518 was also found to inhibit the permeability of valganciclovir and cephalexin. These results suggest that R1518 is a PepT1 substrate as well as an inhibitor.
Fujun Li; Lei Hong; Cheng-I Mau; Rebecca Chan; Than Hendricks; Chuck Dvorak; Calvin Yee; Jason Harris; Tom Alfredson
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  95     ISSN:  0022-3549     ISO Abbreviation:  J Pharm Sci     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-05-01     Completed Date:  2006-07-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1318-25     Citation Subset:  IM    
Copyright Information:
(c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association
Pharmaceutics, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
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MeSH Terms
Amino Acids / pharmacokinetics*
Area Under Curve
Biological Transport
Caco-2 Cells
Cell Membrane Permeability / drug effects
Drug Delivery Systems*
Hydrogen-Ion Concentration
Intestinal Absorption / drug effects
Intestines / metabolism*
Molecular Structure
Monosaccharides / chemistry,  pharmacology
Prodrugs / metabolism*,  pharmacokinetics
Symporters / administration & dosage*
Triazoles / chemistry,  pharmacology
Reg. No./Substance:
0/Amino Acids; 0/Esters; 0/Monosaccharides; 0/PepT1 protein; 0/Prodrugs; 0/Protons; 0/Symporters; 0/Triazoles; 0/levovirin valinate hydrochloride

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