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C. Sharma, IV, T. Velpandian, N. R. Biswas, R. B. Vajpayee, N. Nayak, S. Ghose; Evaluation of Factors Affecting Corneal Permeability for Congeneric Drugs Using Cassette Dosing Technique: An Approach for Preclinical Ophthalmic Drug Discovery. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2445.
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Cassette dosing (N-in-One) is high throughput pharmacokinetic technique. The study evaluated various factors affecting corneal permeability for topically applied congeneric drugs using this technique. Further, a novel QSPR based insilico model was developed to predict corneal permeability using fluoroquinolones as model group.
Sterile cocktail formulations for topically used nine fluoroquinolones (ciprofloxacin, norfloxacin, ofloxacin, pefloxacin, lomefloxacin, levofloxacin, sparfloxacin, gatifloxacin and moxifloxacin) were prepared using cassette dosing technique. Cocktail formulations were prepared at three different concentrations (0.025,0.5&0.1%), further each formulation was adjusted three pH range (4.5,7&8). Each sterile formulation was instilled into rabbit cornea (n=4eyes) at different volumes (12.5,25&50µl). Aqueous humor was aspirated at various intervals through paracentesis after topical anesthesia. All the biosamples were analyzed using LC/MS-MS to determine corneal permeability for each fluoroquinolone. Further, a novel insilico model was developed to predict corneal permeability of topically applied drugs. Various molecular descriptors (n=72) were derived for all fluoroquinolones using different softwares. The applicability of previously reported models to predict corneal permeability for fluoroquinolones was also evaluated.
Various pharmacokinetic parameters like Cmax, Tmax, AUC, Papp were derived all fluoroquinolone using cassette dosing technique. Factors like concentration, pH and volume of instillation of formulation showed pronounced effect on transcorneal permeation. Previously, reported insilico models based upon molecular descriptors like ΔlogP, charge or molecular volume were unable to predict transcorneal penetration of fluoroquinolones. Therefore, a novel QSPR based model was generated using molecular descriptors like logP, pKa, with either GAP or PSA which predicted better corneal permeability as compared to reported models (r=0.940).
Cassette dosing can be well exploited in ophthalmic drug discovery to study pharmacokinetic profile. Various factors have profound affect on corneal permeability of topically applied drugs. The newly developed QSPR model showed better predictability as compared to reported models.
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