PubMed · 6864514
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J G Wagner. 1983. Modified Wagner-Nelson absorption equations for multiple-dose regimens.. https://doi.org/10.1002/jps.2600720531
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In the last decade, poor intestinal absorption of candidate drugs intended for oral administration has been identified as a major bottleneck in drug development. Poor intestinal absorption can often be related to poor aqueous solubility and/or poor permeability across the intestinal wall. Other factors, such as poor stability and the metabolism of the compounds, can also decrease the amount of compound absorbed. In an effort to design compounds with enhanced absorption profile, theoretical predictions of solubility and permeability, among other factors, have gained increased interest, and a large number of papers have been published. In this review, the databases and techniques used for the development of in silico absorption models will be discussed. The focus is on aqueous drug solubility, which has become a major problem in drug development.
The possibility of developing a quantitative relationship between molecular structure and lymphatic transfer of lipophilic compounds co-administered with a long-chain triglyceride vehicle was examined. Molecular descriptors were calculated using the computer program VolSurf, and lymphatic transfer data were derived from the literature. A significant structure-property relationship was established using partial least squares, projection to latent structures statistics (PLS). R(2)X was 0.77, R(2)Y was 0.83 and the prediction power of Q(2) was 0.73 in the two-component PLS model. A number of descriptors contributed to the prediction leading to a complex model, but the prediction power was improved with the PLS model when compared to the frequently used method by relating logP values (LogKow) with lymphatic transfer.
The pre-systemic intestinal extraction ratio (E(g)) has been estimated by an equation based on the well-stirred model, which does not have a term of membrane transport. In this report, we have identified the application limitations of the well-stirred model equation to assess the pre-systemic intestinal extraction ratio. The E(g) of metoprolol (CYP2D6 substrate) was assessed by three methods. Intrinsic clearances for metoprolol metabolism in hepatic and gastrointestinal microsomes were from a published report. Method 1 (model-independent method): the E(g) of 0.228 was obtained according to the equation, F = F(f) x (1 - E(g)) x F(h), where F, F(f) and F(h) were the bioavailability, the fraction entering the intestinal tissue and the hepatic availability, respectively. Method 2: the E(g) of 0.0071 was calculated according to the well-stirred model equation, and was much lower than the value of 0.228. Method 3: the E(g) of 0.213 was obtained by the transport-metabolism-flow (TMF) model equation, and was much closer to the value of 0.228 obtained by the model-independent method than the E(g) of 0.0071 calculated by the well-stirred model equation. Therefore, we propose that the factor of membrane transport process be incorporated into the pharmacokinetic model for the assessment of the pre-systemic intestinal extraction ratio.