Pharmacokinetics and psychotropic drugs.

The current wave of interest in pharmacokinetics of psychotropic drugs has its origins in the writings of Brodie in the years between 1960 and 1970 (for review see Brodie, 1967). Strictly speaking, the science of pharmacokinetics is concerned with rates of transfer of drug molecules within the body. Less strictly, it is the study of drug concentrations in plasma. A lifetime of research in drug analysis, and in the study of drug absorption, metabolism and excretion, had led Brodie to believe that many hitherto poorly controlled drug responses could be brought under control by changing the plasma levels of the drugs concerned. There seemed no reason why this idea should not apply equally to drugs acting on the central nervous system as to drugs affecting other systems, in spite of the bloodbrain barrier, and so Brodie encouraged a number of workers to commence investigations of tranquillizers and antidepressants in this light (Curry & Brodie, 1967; Hammer & Brodie, 1967; Garattini et al. 1973). In the meantime, other workers were investigating lithium (Schou, 1969). However, in spite of more than 10 years of this work, and in spite of the fact that pharmacokinetic control has been a major factor in the use of lithium, fundamental misunderstandings remain. We are repeatedly asked: 'What should we measure, and with what methods?' 'What is the relation with effect?' 'Is there a clinically desirable concentration?' Analytical methods are the oldest problem. Without good methods the work could not start. The major analytical achievements relevant to this work were the application of isotope derivative analysis to tricyclic antidepressants (Hammer & Brodie, 1967), and of gas-chromatography with electron capture detection to phenothiazines, and to benzodiazepines (Curry, 1968; Garattini et al. 1973). Later, combined gas-chromatography/mass spectrometry came prominently into the picture. In the hands of careful workers, these techniques now give reliable data. Provided reasonable precision and accuracy are demonstrated to have been achieved in any laboratory for a specific compound, the exact details of the method used in that laboratory are not important. For instance, at an absurd level, the shape of the test tubes does not matter if the method is proved adequate. However, authors have been able to claim significant modifications by doing obvious things, such as doubling the sample size to double sensitivity. Even so, the complexities are great. For example, chlorpromazine is partially converted to chlorpromazine iV-oxide in the body. Reduction of the metabolite, present in plasma, back to chlorpromazine apparently occurs on storage of samples, and during analytical work-up. Unless strenuous efforts are made to prevent this reduction, inflated chlorpromazine data are obtained. So the chlorpromazine content of the sample may appear to increase on storage or, at best, appear to be erratic, Now, reduction in assay results on storage is all very well, but an increase? I cite this example to demonstrate the need for detailed knowledge of the chemistry involved in such work. Each group of workers should be asked for details of precision and accuracy of methods as used in its own laboratories.