The application of high performance liquid chromatographic (HPLC) methods to the analysis of drugs in plasma was investigated. A method for the analysis in plasma of the diuretic drug, xipamide was developed from first principles. It was based on reversed-phase chromatography following liquid-liquid extraction of the drug and internal standard into diethyl ether. The method was validated and the coefficient of variation for within-day and between-day replicate analyses were 3.1 and 4.8% respectively. In chapter 4, reversed-phase micellar chromatography was used to separate the drugs, chlorthalidone and xipamide. A method was developed for the determination of these drugs in plasma based on 1 iquid-1iquid extraction into diethyl ether followed by chromatography on a Cg- column using an eluent containing 0.05 M sodium dodecyl sulphate. The method was validated and the coefficient of variation for between-day and within-day replicate analyses were 3.1 and 4.6% respectively. In chapter 5, the retention characteristics of basic drugs on an unmodified silica column using reversed-phase eluents were studied. Drug retention as a function of pH was consistent with an ion exchange mechanism of retention. The analytical method, which used an 80% methanolic eluent, was coupled to a column switching arrangement in order to carry out on-line solid-phase extraction of the drugs from plasma. The mean coefficient of variation for 5 replicate analyses of each drug was less than 8%, even without internal standardisation. In chapter 6, the retention characteristics of 31 drugs on an alumina column were investigated. Using reversed-phase eluents, retention mechanisms were found to be similar to those on unmodified silica, consisting principally of ion exchange, as shown by drug retention behaviour with changing pH and ionic strength. The analytical method was coupled to a column switching arrangement and on-line solid-phase extraction was carried out. In chapter 7, the effect of varying the type of column and eluent composition on drug-free plasma profiles was investigated. The study was based on a Cj^g- and a CN- column; methanol and acetonitrile were the organic modifiers used. The plasma profiles were evaluated quantitatively by measuring the number of interfering peaks greater than 2 mm (equivalent to 8 x 10 absorbance units) in the area of interest along the chromatogram. Results were subjected to statistical treatment using a 3-factor analysis of variance design. The three factors were the column, type of organic modifier and either the percent organic modifier, pH or ionic strength. Analysis of the data revealed that significant effects were seen with changing eluent composition, particularly with regard to the percent organic modifier and that the observed effects were strongly dependent on the type of organic modifier and the type of column under consideration.