Drug molecules analysis

Klebe, G., Abraham, U., Mietzner, T. Molecular similarity in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity./. Med. Chem. 1994, 37, 4130-4146. 

Nys, G. G., Rekker, R. F. Statistical analysis of a series of partition coefficients with special reference to the predictability of folding of drug molecules. Introduction of hydrophobic fragmental constants (/-values). Chim. Therap. 1973, 8, 521-535. 

The analysis of absorption data in humans has moved away from the more traditional modeling and data fitting techniques [35]. Absorption processes are now more often characterized by a mean absorption (or input) time (i.e., the average amount of time that the drug molecules spend at the absorption site) or by a process called deconvolution. The former analysis results in a single value (similar to absorption half-life) and the latter results in a profile of the absorption process as a function of time (e.g., absorption rate or cumulative amount absorbed vs. time). These approaches offer additional ways of interpreting the absorption process. 

Capillary electrophoresis (CE) (see Section 3.5) has been used to determine partition coefficients [320-322]. Lipid vesicles or micelles are added to the buffer whose pH is adjusted to different values. Since drug molecules partition to a different extent as a function of pH, the analysis of mobility vs pH data yields log P values. 

An infrequently used method (in pharmaceutical research) for determining the UWL permeability involves measuring transport of molecules across a high-porosity microfilter that is not coated by a lipid. The molecules are able to diffuse freely in the water channels of the microfilter. The filter barrier prevents convective mixing between the donor and acceptor sides, and an UWL forms on each sides of the microfilter. Camenisch et al. [546] measured the effective permeabilities of a series of drug molecules in 96-well microtiter plate-filterplate (Millipore GVHP mixed cellulose ester, 0.22 pm pore) sandwich where the filters were not coated by a lipid. The permeabilities were nearly the same for all the molecules, as shown in Fig. 7.8a. Our analysis of their data, Fig. 7.8b, indicates / aq = 460 pm (sandwich stirred at 150 rpm). We have been able to confirm similar results in our laboratory with different microfilters, using the lipid-free method. 

The chiral separation of drug molecules and of their precursors, in the case of the synthesis of enantiomerically pure drugs, is one of the important application areas of HPLC in pharmaceutical analysis. Besides HPLC, capillary electrophoresis is another technique of choice for chiral separations. In this chapter we give an overview of the different modes (e.g., direct and indirect ones) by which it is possible to obtain a chiral separation in HPLC and CE. The direct approaches, i.e., those where the compound of interest is not derivatized prior to separation, are discussed in more detail since they are the most frequently used... 

It has been recognised for some time (see for example reference 1), that surfactants can increase the rate and extent of transport of solute molecules through biological membranes by fluidisation of the membrane. It is only recently, however, that sufficient work has been carried out to allow some analysis of structure-action relationships. In this overview an attempt is made, by reference to our own work and to work in the literature, to define those structural features in polyoxyethylene alkyl and aryl ethers which give rise to biological activity, especially as it is manifested in interactions with biomembranes and subsequent increase in the transport of drug molecules. 

Structure-activity relationships are generally applied in the pharmaceutical sciences to drug molecules. The value of any structure-activity correlation is determined by the precision of the biological data. So it is with studies of the interaction of nonionic surfactants and biomembranes. Analysis of results is complicated by the difficulty in obtaining data in which one can discern small differences in the activity of closely related compounds, due to i) biological variability in tissues and animals, ii) potential differential metabolism of the surfactants in a homologous series (2), iii) kinetic and dynamic factors such as different rates of absorption of members of the surfactant homologous series (2) and iv) the typically biphasic concentration dependency of nonionic surfactant action (3 ). 

In order to elicit their effect, drug molecules must be bound to the cells of the effector organ. Binding commonly occurs at specific cell structures, namely, the receptors. The analysis of drug binding to receptors aims to determine the affinity of ligands, the kinetics of interaction, and the characteristics of the binding site itself. 

Klebe, G. and Abraham, U. (1993) On the prediction of binding properties of drug molecules by comparative molecular field analysis, foumal of Medicinal Chemistry, 36, 70-80. 

Nevertheless, Hansch analysis revolutionized drug molecule optimization and directly led to two other strategies for molecule optimization the Free-Wilson method and the Topliss decision tree. 

GC detectors can be grouped into concentration-sensitive detectors and mass-sensitive detectors. The signal from a concentration-sensitive detector is related to the concentration of solute in the detector, which does not usually destroy the sample. Mass-sensitive detectors usually destroy the sample, and the signal is related to the rate at which solute molecules enter the detector. The response of a mass-sensitive detector is unaffected by make-up gas, while that of a concentration-sensitive detector will lower with make-up gas. A summary of some important characteristics of the GC detectors specifically used in drug residue analysis is presented in Table 23.1. 

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