Prediction of oral drug absorption in humans by theoretical passive absorption model☆
Introduction
In the recent drug discovery and development process, in silico prediction of absorption, metabolism, distribution, and excretion (ADME) is recognized as a key technique (van de Waterbeemd and Gifford, 2003). Among ADME properties, oral absorption has been most intensively investigated for in silico prediction. As an oral absorption parameter, the fraction of a dose absorbed in humans (Fa%), the effective intestinal membrane permeability in humans (Peff), Caco-2 permeability, etc., have been studied as targets for in silico prediction (Wessel et al., 1998, Winiwarter et al., 1998, Zhao et al., 2001, Yamashita et al., 2002). Oral absorption from a solid dosage is determined by the dissolution rate, the solubility, and the intestinal membrane permeability (Yu and Amidon, 1999). Intestinal membrane permeation consists of transcellular, paracellular, and unstirred water layer (UWL) permeation. Most of the previous in silico prediction studies scrambled these absorption processes, and the contribution of each process cannot be predicted. In addition, the previous in silico methods often used descriptors that are not easy to translate into better drug design.
Previously, the theoretical passive absorption model (TPAM) had been proposed for describing passive intestinal membrane permeation (Camenisch et al., 1996, Camenisch et al., 1998). The TPAM consists of three partial models, i.e., the transcellular, paracellular and UWL permeation models. The TPAM is beneficial for qualitatively comprehending the membrane permeation from the viewpoint of both the physiology of the intestine and the chemical structure of drugs. However, the predictability of the TPAM for the oral absorption in humans has not been examined. The purpose of the present study was to quantitatively examine the oral drug absorption predictability of the TPAM.
Section snippets
Transcellular permeation model
Passive transcellular permeation is diffusion across a lipid bilayer. Therefore, the permeability depends on the lipophilicity of the permeant. In the previous TPAM, the passive transcellular permeability (Ptrans) was expressed by the 1-octanol/buffer distribution coefficient (Dow), with the help of so-called Collander equations (Collander, 1950, Collander, 1951, Camenisch et al., 1998).
To reflect the pH at the intestinal epithelial membrane surface, the Dow at pH 6.0 was employed (
Results and discussion
Previously, Wenlock et al. (2003) reported that the mean log Dow (pH 7.4) of the marketed oral drugs was 1.0 and the standard deviation was 3.4. Distribution of log Dow (pH 7.4) and electrical charge of drugs collected in this study (N = 343) is shown in Fig. 1. The mean log Dow (pH 7.4) was −0.41 and the standard deviation was 3.3. After excluding efflux substrates, intestinal metabolism substrates and low solubility drugs, the mean log Dow (pH 7.4) was −0.62 and the standard deviation was 2.8 (N =
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Part of this study was presented at LogP2004 Symposium, Zurich (Sugano, K., Obata, K., Saitoh, R., Higashida, A., Hamada, H., 2004. Processing of biopharmaceutical profiling data in drug discovery).
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Present address: Global Research & Development, Nagoya Laboratories, Pharmaceutical Sciences, Science and Technology, Pharmaceutical R&D, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.