Modulation of P-glycoprotein-mediated efflux by prodrug derivatization: an approach involving peptide transporter-mediated influx across rabbit cornea.
The aim of this study was to investigate the modulation of efflux mechanisms using transporter- targeted prodrug derivatization of a model P-gp substrate, quinidine. The L-valine, L-valine-valine esters of quinidine, val-quinidine (VQ), and val-val-quinidine (VVQ) were synthesized in our laboratory, respectively. [(14)C] erythromycin was chosen to delineate the affinity of quinidine (Q) toward P-gp. [(3)H] glycylsarcosine (GS, or glysar) was chosen as a model peptide transporter (PEPT) substrate. Uptake studies were performed on rPCEC (rabbit primary corneal epithelial culture) using 12-well plates. Transport studies were conducted with isolated rabbit corneas at 34 degrees C. Efflux of [(14)C] erythromycin was significantly increased in the presence of quinidine, whereas it was unaltered in the presence of VQ and VVQ. VVQ was more stable, both in buffers and tissue homogenate. Transport of VQ and VVQ was inhibited with GS, and their permeability values were 1.5 and 3 times higher than the permeability of quinidine, respectively. Results from this study clearly indicate that prodrug derivatization of quinidine can modulate P-gp-mediated efflux. These prodrugs have a reduced or diminished affinity toward P-gp and were further recognized by the peptide transporter- mediated process. Enhanced permeabilities of the prodrugs indicate that drug derivatization can be a viable strategy for overcoming P-gp-mediated efflux.
Katragadda
Suresh
S
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA.
Talluri
Ravi S
RS
Mitra
Ashim K
AK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D003315:Cornea / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D015394:Molecular Structure; D010539:Permeability; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D011802:Quinidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D026901:Membrane Transport Proteins; D011355:Prodrugs; C043912:peptide permease; D011802:Quinidine