Exploring the role of different drug transport routes in permeability screening

Center of Pharmaceutical Informatics, Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Journal of Medicinal Chemistry (Impact Factor: 5.48). 02/2005; 48(2):604-13. DOI: 10.1021/jm049711o
Source: PubMed

ABSTRACT The influence of different drug transport routes in intestinal drug permeability screening assays was studied. Three experimental models were compared: the small-intestine-like 2/4/A1 cell model, which has a leaky paracellular pathway, the Caco-2 cell model, which has a tighter paracellular pathway, and artificial hexadecane membranes (HDMs), which exclusively model the passive transcellular pathway. The models were investigated regarding their ability to divide passively and actively transported compounds into two permeability classes and to rank compounds according to human intestinal absorption. In silico permeability models based on two-dimensional (2D) and three-dimensional (3D) molecular descriptors were also developed and validated using external test sets. The cell-based models classified 80% of the acceptably absorbed compounds (FA >/= 30%) correctly, compared to 60% correct classifications using the HDM model. The best compound ranking was obtained with 2/4/A1 (r(s) = 0.74; r(s) = 0.95 after removing actively transported outliers). The in silico model based on 2/4/A1 permeability gave results of similar quality to those obtained when using experimental permeability, and it was also better than the experimental HDM model at compound ranking (r(s) = 0.85 and 0.47, respectively). We conclude that the paracellular transport pathway present in the cell models plays a significant role in models used for intestinal permeability screening and that 2/4/A1 in vitro and in silico models are promising alternatives for drug discovery permeability screening.

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    • "Since Caco-2 monolayers can withstand quite vigorous stirring conditions, good estimates of passive permeability coefficients in the vicinity of those observed in human in vivo can be obtained (Artursson and Karlsson, 1991; Lennernäs et al., 1996). For compounds displaying an intermediate passive permeability , it is more difficult to predict the intestinal permeability in vivo since in all systems, including the perfused human intestine, there is a steep relationship between permeability and absorption (Lennernäs, 1998; Matsson et al., 2005). In this permeability range, compounds tend to be more polar and have a slower distribution into the cell membranes and/or they may be subjected to active transport processes. "
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    • "compounds used here , the variation of FA data from different sources was quite limited ( less than 15% ) . The only exception was verapamil , for which FA was generally identified in the range 95 – 100% ( Matsson et al . , 2005 ; Zhao et al . , 2001 ; Kansy et al . , 1998 ; Shin et al . , 2009 ) , except for one value of 28% ( Varma et al . , 2004 ) . Being verapamil a substrate for P - gp , its FA may be affected by individual differences in the P - gp activity . Indeed , in vivo data related to actively transported chemicals could be strongly dependent on th"
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    • "The permeability of confluent cell monolayers to soluble factors is also studied using transwell devices [5]. For example, the ability of small molecules to pass culture models of the intestinal lining is one important indicator of the efficacy of drug candidates [6]. The membranes used in transwells are typically 'track-etched' membranes created by bombarding sheets of dense polycarbonate (PC) or polyester-sulfone (PES) with subatomic particles to fracture the polymer backbone. "
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