1997 Fiscal Year Final Research Report Summary
Construction of new method for predicting intestinal drug absorption considering electrostatic interaction with biological membrane
| Project/Area Number |
07457547
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | Hokkaido University |
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Principal Investigator |
MIYAZAKI Katsumi Hokkaido Univ., Medical Hospital, Professor, 医学部・付属病院, 教授 (30166144)
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| Project Period (FY) |
1995 – 1997
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| Keywords | intestinal absorption / lipophylicity / hydrogen-bounding / membrane permeation / electrostatic interaction |
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| Research Abstract |
A general method for predicting the intestinal absorption of a wide range of drugs using multiple regression analysis of their physicochemical properties and the drug-membrane electrostatic interaction was developed. The absorption rates of tested drugs from rat jejunum were measured by in situ single-pass perfusion technique. When the analysis was applied to each respective group of drugs (i.e., anionic, cationic and non-ionized compounds), good regression coefficients were obtained by using organic solvent/buffer partition coefficient (lipophilicity) and permeation rate across artificial membranes (silicon and EVA membrane). However, a poor correlation was obteined when these three groups of drugs were put together for prediction. Meanwhile, this poor correlation was improved remarkably when drug-membrane electrostatic interaction, namely, hydrogen-bonding donor (H_<alpha>) and acceptor (H_<beta>) activity or index of electricity (E_C) were added to other parameters of lipophilicity and permeation rate across artificial membranes. Moreover, the equation obtained from these regression analyzes was applicable even to the prediction of the absorption of the zwitter-ionic drugs. These results suggest that including the electrostatic interaction parameters in addition to lopophilicity and permeability across artificial membranes would afford a better prediction for the intestinal absorption of the vast majority of drugs.
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