Abstract
Aim:
To derive a theoretical model for the prediction of corneal permeability of miscellaneous organic compounds in drug design.
Methods:
A training set of 28 structurally diverse compounds was used to build up the membrane-interaction quantitative structure-activity relationship (MI-QSAR) models. Intermolecular and intramolecular solute descriptors were computed using molecular mechanics, molecular dynamics simulations and quantum chemistry. The QSAR models were optimized using multidimensional linear regression fitting and a stepwise method. A test set of 8 compounds was evaluated using the models as part of a validation process.
Results:
Significant MI-QSAR models (R=0.976, S=0.1301, F=70.957) of corneal permeability of organic compounds were constructed. Corneal permeability was found to depend upon the sum of net atomic charges of hydrogen atoms attached to the heteroatoms (N, O), the sum of the absolute values of the net atomic charges of oxygen and nitrogen atoms, the principal moment of inertia (X), the Connolly accessible area and the conformational flexibility of the solute-membrane complex.
Conclusion:
The MI-QSAR models indicated that the corneal permeability of organic molecules was not only influenced by the organic solutes themselves, but also related to the properties of the solute-membrane complex, that is, the interactions of the molecule with the phospholipid-rich regions of cellular membranes.
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References
Davies NM . Biopharmaceutical considerations in topical ocular drug delivery. Clin Exp Pharmacol Physiol 2000; 27: 558–62.
Ahmed I, Patton TF . Disposition of timolol and insulin in the rabbit eye following corneal versus noncorneal absorption. Int J Pharm 1987; 38: 9–21.
Kumar MT, Pandit JK, Balasubramaniam J . Novel therapeutic approaches for uveitis and retinitis. J Pharm Pharm Sci 2001; 4: 248–54.
Toropainen E, Ranta VP, Talvitie A, Suhonen P, Urtti A . Culture model of human corneal epithelium for prediction of ocular drug absorption. Invest Ophthalmol Vis Sci 2001; 42: 2942–8.
Maurice DM, Mishima S . Ocular pharmacokinetics. In: Sears MC . vol 69. Handbook of experimental pharmacology. Pharmacology of the eye. Berlin: Springer-Verlag; 1984. p 19–116.
Schornwald RD . Ocular drug delivery. Pharmacokinetic considerations. Clin Pharmacokinet 1990; 18: 255–69.
Liaw J, Robinson JR . Ocular penetration enhancers. In: Mitra AK Ophthalmic drug delivery system. New York: Marcel Dekker; 1993. p 369–81.
Borchardt RT . Assessment of transport barriers using cell and tissue culture systems. Drug Dev Ind Pharm 1990; 16: 2595–612.
Schoenwald RD, Huang HS . Corneal penetration behavior of beta-blocking agents I: physiochemical factors. J Pharm Sci 1983; 72: 1266–72.
Liaw J, Robinson JR . The effect of polyethylene glycol molecular weight on corneal transport and the related influence of penetration enhancers. Int J Pharm 1992; 88: 125–40.
Liaw J, Rojanasakul Y, Robinson JR . The effect of drug charge type and charge density on corneal transport. Int J Pharm 1992; 88: 111–24.
Sieg JW, Robinson JR . Vehicle effects on ocular drug bioavailability II: evaluation of pilocarpine. J Pharm Sci 1977; 66: 1222–8.
Maren TH, Jankowska L . Ocular pharmacology of sulfonamides: the cornea as barrier and depot. Curr Eye Res 1985; 4: 399–408.
Wei G, Xu H, Ma Y, Li SM, Zheng JM . Effect of pH on the permeability of timolol maleate across isolated rabbit cornea. Acta Pharm Sin 2001; 36: 707–10.
Shih RL, Lee VHL . Rate limiting barrier to the penetration of ocular hypotensive beta blockers across the corneal epithelium in the pigmented rabbit. J Ocul Pharmacol 1990; 6: 329–36.
Loftssona T, Jarvinen T . Cyclodextrins in ophthalmic drug delivery. Adv Drug Deliv Rev 1999; 36: 59–79.
Schoenwald RD, Ward RL . Relationship between steroid permeability across excised rabbit cornea and octanol-water partition coefficients. J Pharm Sci 1978; 67: 786–8.
Grass GM, Robinson JR . Mechanisms of corneal drug penetration: in vivo and in vitro kinetics. J Pharm Sci 1988; 77: 3–17.
Yoshida F, Topliss JG . Unified model for the corneal permeability of related and diverse compounds with respect to their physicochemical properties. J Pharm Sci 1996; 85: 819–23.
Fu XC, Liang WQ . A simple model for the prediction of corneal permeability. Int J Pharm 2002; 232: 193–7.
Iyer M, Mishra R, Han Y, Hopfinger AJ . Predicting blood-brain barrier partitioning of organic molecules using membrane-interaction QSAR analysis. Pharm Res 2002; 19: 1611–21.
Ma XL, Chen C, Yang J . Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharmacol Sin 2005; 26: 500–12.
Hauser H, Pascher L, Pearson RH, Sundell S . Preferred conformation and molecular packing of phosphatidylethanolamine and phosphatidylcholine. Biochem Biophys Acta 1981; 650: 21–51.
van der Ploeg P, Berendsen HJC . Molecular dynamics simulation of a bilayer membrane. J Chem Phys 1982; 76: 3271–6.
Stouch TR . Lipid membrane structure and dynamics studied by all atom molecular dynamics simulations of hydrated phosphatidylcholine vesicles. Mol Simulation 1993; 1: 335–62.
Abraham MH, Martins F, Mitchell RC . Algorithms for skin permeability using hydrogen bond descriptors: the problem of steroids. J Pharm Pharmacol 1997; 49: 858–65.
Fu XC, Yu QS, Liang WQ . A modified mathematical model for percutaneous absorption of drugs. Chin Pharm J 2000; 35: 276–7.
Clark DE . Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena 1. Prediction of intestinal absorption. J Pharm Sci 1999; 88: 807–14.
van de Waterbeemd H, Camenish G, Folkers G, Raevsky OA . Estimation of Caco-2cell permeability using calculated molecular descriptors. Quant Struct Act Relat 1996; 15: 480–90.
Fu XC, Liang WQ, Yu QS . Correlation of drug absorption with molecular charge distribution. Pharmazie 2001; 56: 267–8.
Norinder U, Sjoberg P, Osterberg T . Theoretical calculation and prediction of brain-blood partitioning of organic solutes using Molsurf parameterization and PLS statistics. J Pharm Sci 1998; 87: 952–9.
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Project supported by the National Natural Science Foundation of China (No 30171094 and No 30271497).
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Chen, C., Yang, J. MI-QSAR models for prediction of corneal permeability of organic compounds. Acta Pharmacol Sin 27, 193–204 (2006). https://doi.org/10.1111/j.1745-7254.2006.00241.x
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DOI: https://doi.org/10.1111/j.1745-7254.2006.00241.x