title: Vitreal kinetics of quinidine in rabbits in the presence of topically coadministered P-glycoprotein substrates/modulators.
abstract: The purpose of this study was to investigate whether topically administered P-glycoprotein (P-gp) substrates/modulators can alter vitreal kinetics of intravitreally administered quinidine. Male New Zealand rabbits were used under anesthesia. Vitreal kinetics of intravitreally administered quinidine (0.75-microg dose) was determined alone and in the presence of verapamil (coadministered topically/intravitreally) or prednisolone hemisuccinate sodium (PHS) (coadministered topically). In the presence of topically instilled verapamil (1% w/v), elimination half-life (t(1/2)) (176 +/- 7 min), apparent elimination rate constant (lambda(z)) (0.0039 +/- 0.0001 min(-1)), and mean retention time (MRT) (143 +/- 30 min) of intravitreally administered quinidine were significantly different from those of the control (105 +/- 11 min, 0.0066 +/- 0.0007 min(-1), and 83 +/- 13 min, respectively). A 2-fold increase in the t(1/2) with a corresponding decrease in lambda(z) and a 1.5-fold increase in the MRT of quinidine were observed in the presence of topically coadministered 2% w/v PHS. Intravitreal coadministration of quinidine and verapamil resulted in a significant increase in t(1/2) (159 +/- 9 min) and a decrease in lambda(z) (0.0043 +/- 0.0002 min(-1)) of quinidine. The vitreal pharmacokinetic parameters of sodium fluorescein, alone or in the presence of topically instilled verapamil, did not show any statistically significant difference, indicating that ocular barrier integrity was not affected by topical verapamil administration. Results from this study suggest that topically applied P-gp substrates/modulators can alter vitreal pharmacokinetics of intravitreally administered P-gp substrates, possibly through the inhibition of P-gp expressed on the basolateral membrane of the retinal pigmented epithelium.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. majumso@olemiss.edu
authors.forename: Soumyajit
authors.initials: S
authors.lastname: Majumdar
authors.forename: Ketan
authors.initials: K
authors.lastname: Hippalgaonkar
authors.forename: Ramesh
authors.initials: R
authors.lastname: Srirangam
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000287:Administration, Topical; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D004347:Drug Interactions; D004917:Erythromycin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019793:Fluorescein / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006207:Half-Life; D008297:Male; D008657:Metabolic Clearance Rate; D009883:Ophthalmic Solutions; D011239:Prednisolone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011802:Quinidine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011817:Rabbits; D014018:Tissue Distribution; D014700:Verapamil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014822:Vitreous Body / Q000187:drug effects* / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D009883:Ophthalmic Solutions; D004917:Erythromycin; D011239:Prednisolone; D014700:Verapamil; C021322:prednisolone hemisuccinate; D011802:Quinidine; D019793:Fluorescein