title: Stereoselective evasion of P-glycoprotein, cytochrome P450 3A, and hydrolases by peptide prodrug modification of saquinavir.
abstract: 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.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Wang
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Pal
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001711:Biotransformation; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008954:Models, Biological; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019258:Saquinavir / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D013678:Technology, Pharmaceutical / Q000379:methods; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D011355:Prodrugs; D051544:Cytochrome P-450 CYP3A; D006867:Hydrolases; D014633:Valine; D019258:Saquinavir