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 (t1/2) (176 ± 7 min), apparent elimination rate constant (λz) (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 t1/2 with a corresponding decrease in λz 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 t1/2 (159 ± 9 min) and a decrease in λz (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.
Footnotes
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This work was supported by the National Institutes of Health National Eye Institute [Grant EY018426-02].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.026450.
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ABBREVIATIONS: RPE, retinal pigmented epithelium; P-gp, P-glycoprotein; PHS, prednisolone hemisuccinate sodium; IPBS, isotonic phosphate buffer saline; HPLC, high-performance liquid chromatography; AUMC, area under the statistical moment curve; MRT, mean retention time; AUC, area under the curve.
- Accepted April 29, 2009.
- Received January 6, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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