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T. Velpandian, S. Senthil Kumari, N.R. Biswas, S. Ghose; Role of P–Glycoprotein (p–gp) on the Pharmacokinetics of Intravitreally Injected P–gp Substrate in Rabbits . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3762.
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The purpose of this study was to evaluate the involvement of P–gp drug transporters in retina in the pharmacokinetics of intravitreally injected P–gp substrate (Rhodamine 123 – a fluorescent marker) in presence or absence of its specific inhibitor.
After getting the approval from the Institutional Animal Ethics Committee, twenty–four albino rabbits of either sex weighing 1.5–2.5 kg body weight were randomized into two groups of twelve rabbits each. Group I received intravitreal injections of Rhodamine 123 (Rho 123) at the dose of 350ng in 0.05 ml. Group II animals received intravenous injection of GF 120918 (P–gp inhibitor) at the dose of 3.5 mg/kg via marginal ear vein 30 minutes before the intravitreal injection of Rho 123. Rabbits were anesthetized with sodium pentobarbital at the dose of 30mg/kg i.v (corneal anesthesia was achieved with 4% topical xylocaine. Before the intravitreal administration of Rho 123, 0.05ml aqueous humor was aspirated by paracentesis through limbus. At different time points (15, 30, 60, 120, 240 &360 mins), the animals were sacrificed with excess of sodium pentobarbital anesthesia. Eyes were enucleated and four eyes were used for each time point. The plasma was separated by standard procedure from blood samples collected in EDTA vials by cardiac puncture. The ocular tissues (cornea, conjunctiva, lens, aqueous, iris, vitreous, sclera, choroid and retina) were separated from the frozen eyes according to the procedure described by Abel & Boyle (1976). The separated samples were weighed accurately in the pre–weighed tubes and stored at –70oC till analysis by HPLC.
In Group II, the AUC0–t (hr*µg.ml–1) of Rho 123 in cornea, conjunctiva, aqueous, lens, iris, vitreous, sclera, choroid and retina was found to be 2.4, 1.5,1.2, 2.0, 1,1.6, 2.1, 2 and 1.6 times respectively higher than that of Group I.
To conclude, using Rho123 as a surrogate marker for P–glycoprotein efflux pump, this study indicates the involvement of p–gp drug transporters in the intravitreal kinetics. Further studies are in progress using microdialysis probes to confirm the same.
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