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-μg 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 (λ_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 λ_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 λ_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.