Cellular drug permeability

While the presence of surfactants is advantageous due to an increase in cellular membrane permeability, which facilitates drug absorption and bioavailability [218], caution needs to be taken in relation to the amount of surfactant incorporated, as high concentrations can lead to ocular toxicity. In general, nonionic surfactants are preferred over ionic ones, which are generally too toxic to be used in ophthalmic... 

Lacombe, O. Woodley, J. Solleux, C. Delbos, J. M. Boursier-Neyret, C. Houin, G. Localisation of drug permeability along the rat small intestine, using markers of the paracellular, trans-cellular and some transporter routes, Eur.f Pharm. Sci. 2004, 23 (4-5), 385-391. 

If initial solute uptake rate is determined from intestinal tissue incubated in drug solution, uptake must be normalized for intestinal tissue weight. Alternative capacity normalizations are required for vesicular or cellular uptake of solute (see Section VII). Cellular transport parameters can be defined either in terms of kinetic rate-time constants or in terms of concentration normalized flux [Eq. (5)]. Relationships between kinetic and transport descriptions can be made on the basis of information on solute transport distances. Note that division of Eq. (11) or (12) by transport distance defines a transport resistance of reciprocal permeability (conductance). 

Molecules with a large molecular weight or size are confined to the transcellular route and its requirements related to the hydrophobicity of the molecule. The transcellular pathway has been evaluated for many years and is thought to be the main route of absorption of many drugs, both with respect to carrier-mediated transport and passive diffusion. The most well-known requirement for the passive part of this route is hydrophobicity, and a relationship between permeability coefficients across cell monolayers such as the Caco-2 versus log P and log D 7.4 or 6.5 have been established [102, 117]. However, this relationship appears to be nonlinear and reaches a plateau at around log P of 2, while higher lipophilicities result in reduced permeability [102, 117, 118]. Because of this, much more attention has recently been paid towards molecular descriptors other than lipophilicity [86, 119-125] (see section 5.5.6.). The relative contribution between the para-cellular and transcellular components has also been evaluated using Caco-2 cells, and for a variety of compounds with different charges [110, 112] and sizes [112] (see Section 5.4.5). 

From an industrial perspective, quantitative knowledge of the existence of different transporters within the cellular system used in screening procedures is of major importance as it can influence both the predictive value of the permeability coefficients and interpretation of the results. In addition, information on species differences or similarities or discrepancies between cell culture models and animals now provide an important basis for the scaling of data during the early phases of drug discovery for animals or humans [48]. 

Conradi RA, Burton PS and Borchardt RT (1996) Physiochemical and Biological Factors That Influence a Drug s Cellular Permeability by Passive Diffusion. In V Pliska, B Testa, H Van De Waterbeemd (Eds.), Lipophilicity in Drug Action and Toxicology. Weinheim, VCH, pp 233-252. 

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