-2-101234 log Kd (pH 7.4, octanol-water)

Figure 7.24 Membrane retention in octanol-soaked filters versus octanol-water apparent partition coefficients.

monolayers in the presence of various levels of serum proteins, and observed 6585% retentions of the drug molecule by the MDCK cells. Wils et al. [591] reported retentions as high as 44% in Caco-2 cells. In a later publication, Sawada et al. [575] cited values as high as 89% for a homologous series of lipophilic molecules. Krishna et al. [551] more recently reported Caco-2 permeability results for lipophilic molecules, including progesterone and propranolol. They found retentions as high as 54%. It is undoubtedly a common phenomenon with research compounds, which are often very lipophilic. Yet in most reported assays, the effect is ignored, it appears. Ho et al. [514] derived an equation [similar to Eq. (7.22)] to describe the phenomenon in cultured cells, but its application in cultured-cell assays is scarce so far.

Retention may be a good predictor of the PK volume of distribution, of protein binding [264,592] or possibly even of conditions suitable for P-gp binding and extrusion of drugs. Apparently, these themes have not yet been adequately explored.

It is curious that the log of the expression for R, Eq. (7.18), produces a ''Kubinyi-like'' bilinear equation logR = log Kd — log(rKd + 1) + log r (7.45)

where the oil-water volume ratio, r = VM/(VA + VD). Its form is essentially that of Eq. (7.44). When 2% DOPC in dodecane is used for the PAMPA membrane lipid, VM could be taken as the volume of dodecane (4- 6 pL) or the volume of DOPC

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