Majumdar S, Hippalgaonkar K, Srirangam R
Vitreal Kinetics of Quinidine in Rabbits in the Presence of Topically Co-administered P-gp Substrates/Modulators. [JOURNAL ARTICLE]
Drug Metab Dispos 2009 Apr 30.
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 (co-administered topically/intravitreally) or prednisolone hemisuccinate sodium (PHS, co-administered topically). In the presence of topically instilled verapamil (1% w/v), elimination half-life (t1/2) (176 +/- 7 min), apparent elimination rate constant (lambdaz) (0.0039 +/- 0.0001 min(-1)) and mean retention time (MRT) (143 +/- 30 min) of intravitreally administered quinidine were significantly different from that of control (105 +/- 11 min, 0.0066 +/- 0.0007 min(-1) and 83 +/- 13 min, respectively). A 2-fold increase in the t1/2 with a corresponding decrease in lambdaz and a 1.5-fold increase in the MRT of quinidine was observed in the presence of topically co-administered 2%w/v PHS. Intravitreal co-administration of quinidine and verapamil resulted in a significant increase in the t1/2 (159 +/- 9 min) and a decrease in the lambdaz (0.0043 +/- 0.0002 min(-1)) of quinidine. 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 suggests that topically instilled 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.
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