title: Interaction between topically and systemically coadministered P-glycoprotein substrates/inhibitors: effect on vitreal kinetics.
abstract: The objective of the present study was to investigate the effect of topically coadministered P-glycoprotein (P-gp) substrates/inhibitors on the vitreal kinetics of a systemically administered P-gp substrate. Anesthetized male rabbits were used in these studies. The concentration-time profile of quinidine in the vitreous humor, after intravenous administration, was determined alone and in the presence of topically coadministered verapamil, prednisolone sodium phosphate (PP), and erythromycin. The vitreal pharmacokinetic parameters of quinidine in the presence of verapamil [apparent elimination rate constant (λ(z)), 0.0027 ± 0.0002 min(-1); clearance (CL_F), 131 ± 21 ml/min; area under the curve (AUC(0-∞)), 39 ± 7.0 μg · min/ml; and mean residence time, 435 ± 20 min] were significantly different from those of the control (0.0058 ± 0.0006 min(-1), 296 ± 46 ml/min, 17 ± 3 μg · min/ml, and 232 ± 20 min, respectively). A 1.7-fold decrease in the vitreal λ(z) and a 1.5-fold increase in the vitreal AUC of quinidine were observed in the presence of topical PP. Statistically significant differences between the vitreal profiles of the control and erythromycin-treated group were also observed. Plasma concentration-time profiles of quinidine, alone or in the presence of the topically instilled compounds, remained unchanged, indicating uniform systemic quinidine exposure across groups. This study demonstrates an interaction between topically and systemically coadministered P-gp substrates, probably through the modulation of P-gp on the basolateral membrane of the retinal pigmented epithelium, leading to changes in the vitreal kinetics of the systemically administered agent.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
authors.forename: Ketan
authors.initials: K
authors.lastname: Hippalgaonkar
authors.forename: Ramesh
authors.initials: R
authors.lastname: Srirangam
authors.forename: Bharathi
authors.initials: B
authors.lastname: Avula
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
authors.forename: Soumyajit
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000287:Administration, Topical; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004917:Erythromycin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D017551:Microdialysis; D009883:Ophthalmic Solutions; D011239:Prednisolone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011802:Quinidine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011817:Rabbits; D013379:Substrate Specificity; D013997:Time Factors; D014018:Tissue Distribution; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014822:Vitreous Body / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009883:Ophthalmic Solutions; D004917:Erythromycin; C009022:prednisolone phosphate; D011239:Prednisolone; D014700:Verapamil; D011802:Quinidine