Pharmacokinetics drug-membrane interactions

Tab. 4.36 Comparison of the physical properties of drug-membrane interactions and their pharmacokinetics. (Reprinted from Tab. 1 of ref. 125 with permission from Academic Press)...

Further support for the thesis that the observed drug-membrane interaction directly or indirectly affects the receptor and does not represent pharmacokinetic influences can be derived from preliminary data of a small set of five derivatives for which some pharmacokinetic parameters were determined in rats [41]. The pharmacokinetic parameters - area under the curve (AUC), elimination rate constant (kd ), half-life (to 5), the time of maximal concentration (tmax), and maximal concentration (cmax) - did not correlate significantly with either log 1/ED50(MES), log Al/T2, or log fC0i t. Instead, even for this small set of compounds, log 1 /ED50(MES) correlated again significantly with both parameters log Al/T2 and log K ocL (r = 0.998 and 0.973 respectively). 

It can be concluded that no significant differences exist between anticonvulsive and neurotoxic effects for this series of derivatives. The variation in the anticonvulsive effect seems to be determined by drug-membrane interactions and not by the pharmacokinetics of these compounds. 

Only in special cases, e.g. in enzyme inhibition, is an isolated process measured and described. In the case of membrane-bound receptors, the drug-membrane interaction may influence the ligand binding to the active site (compare chapter 1.2). In other biological systems, like in cells, isolated organs, or whole animal data, much more complex relationships are to be expected, an exception being pharmacokinetic data, where only rate constants or concentrations of different drugs in certain compartments are described in a quantitative manner. 

The aims of this book are to highlight and summarize for medicinal and pharmaceutical chemists some important properties of phospholipid bilayers to explain, using examples, analytical tools for determining thermotropic and dynamic membrane properties and the possible effects of drugs on such membrane properties and, finally, to discuss examples of the importance of drag-membrane interactions for drug pharmacokinetics (absorption, distribution, accumulation) as well as drag efficacy, selectivity, and toxicity. 

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