Browsing by Subject "PIGMENTED RABBIT"

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  • Ramsay, Eva; del Amo, Eva M.; Toropainen, Elisa; Tengvall-Unadike, Unni; Ranta, Veli-Pekka; Urtti, Arto; Ruponen, Marika (2018)
    On the surface of the eye, both the cornea and conjunctiva are restricting ocular absorption of topically applied drugs, but barrier contributions of these two membranes have not been systemically compared. Herein, we studied permeability of 32 small molecular drug compounds across an isolated porcine cornea and built a quantitative structure-property relationship (QSPR) model for the permeability. Corneal drug permeability (data obtained for 25 drug molecules) showed a 52-fold range in permeability (0.09-4.70x10(-6) cm/s) and the most important molecular descriptors in predicting the permeability were hydrogen bond donor, polar surface area and halogen ratio. Corneal permeability values were compared to their conjunctival drug permeability values. Ocular drug bioavailability and systemic absorption via conjunctiva were predicted for this drug set with pharmacokinetic calculations. Drug bioavailability in the aqueous humour was simulated to be <5% and trans-conjunctival systemic absorption was 34-79% of the dose. Loss of drug across the conjunctiva to the blood circulation restricts significantly ocular drug bioavailability and, therefore, ocular absorption does not increase proportionally with the increasing corneal drug permeability.
  • Balla, Anusha; Auriola, Seppo; Grey, Angus C.; Demarais, Nicholas J.; Valtari, Annika; Heikkinen, Emma M.; Toropainen, Elisa; Urtti, Arto; Vellonen, Kati-Sisko; Ruponen, Marika (2021)
    Ocular drug absorption after eye drop instillation has been widely studied, but partitioning phenomena and spatial drug distribution are poorly understood. We investigated partitioning of seven beta-blocking drugs in corneal epithelium, corneal stroma, including endothelium and conjunctiva, using isolated porcine tissues and cultured human corneal epithelial cells. The chosen beta-blocking drugs had a wide range (-1.76-0.79) of n-octanol/buffer solution distribution coefficients at pH 7.4 (Log D-7.4). In addition, the ocular surface distribution of three beta-blocking drugs was determined by matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) after their simultaneous application in an eye drop to the rabbits in vivo. Studies with isolated porcine corneas revealed that the distribution coefficient (K-p) between the corneal epithelium and donor solution showed a positive relationship and good correlation with Log D-7.4 and about a 50-fold range of K-p values (0.1-5). On the contrary, K-p between corneal stroma and epithelium showed an inverse (negative) relationship and correlation with Log D-7.4 based on a seven-fold range of K-p values. In vitro corneal cell uptake showed a high correlation with the ex vivo corneal epithelium/donor K-p values. Partitioning of the drugs into the porcine conjunctiva also showed a positive relationship with lipophilicity, but the range of K-p values was less than with the corneal epithelium. MALDI-IMS allowed simultaneous detection of three compounds in the cornea, showed data in line with other experiments, and revealed uneven spatial drug distribution in the cornea. Our data indicate the importance of lipophilicity in defining the corneal pharmacokinetics and the K-p values are a useful building block in the kinetic simulation models for topical ocular drug administration.