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1. J Pharm Sci. 2012 May 18. doi: 10.1002/jps.23193. [Epub ahead of print]

Stereoselective evasion of P-glycoprotein, cytochrome P450 3A, and hydrolases by
peptide prodrug modification of saquinavir.

Wang Z, Pal D, Mitra AK.

Division of Pharmaceutical Sciences, School of Pharmacy, University of
Missouri-Kansas City, Kansas City, Missouri 64108.

In an approach to overcome biological barriers mediated by P-glycoprotein (P-gp)
and cytochrome P450 3A (CYP3A), a series of stereoisomeric valine-valine prodrugs
of saquinavir (SQV) were synthesized and investigated with respect to affinity
for efflux pump P-gp, and resistance to oxidative and hydrolytic enzymes.
Cellular uptake and bidirectional transport in Caco-2 cells indicated that all
peptide SQV conjugates can bypass P-gp-mediated efflux significantly, regardless
of stereochemistry in promoieties. In comparison with d-configuration,
l-configuration was favored for the interaction between prodrugs and rat hepatic
CYP3A enzymes, and resulted in a relatively rapid clearance by CYP3A. Elimination
half-life of SQV in rat liver microsomes was prolonged dramatically by sevenfold
to 40-fold because of the prodrug modification with the rank order of
d-valine-d-valine-SQV > d-valine-l-valine-SQV > l-valine-d-valine-SQV >
l-valine-l-valine-SQV > d-valine-SQV > l-valine-SQV > SQV. Results of hydrolysis
studies performed in rat intestinal homogenates and plasma indicated that
prodrugs attached with d-valine exhibited significantly reduced biodegradation.
In conclusion, the enhanced transepithelial accumulation and enzymatic stability
observed by SQV peptide prodrug modification are found to be stereoselective.
Specific stereoisomeric dipeptide prodrugs with optimized metabolic stability can
be employed to improve oral bioavailability of SQV. © 2012 Wiley Periodicals,
Inc. and the American Pharmacists Association J Pharm Sci.

Copyright © 2012 Wiley Periodicals, Inc.

PMID: 22611042 [PubMed - as supplied by publisher]