Determination of 2-n-octadecylindole-5-carboxylic acid in human plasma by high-performance liquid chromatography.

A method is described for the determination of the novel hypocholesterolaemic drug, 2-n-octadecylindole-5-carboxylic acid (I) in plasma. A homologue of I is used as the internal standard. Methanol is added to the plasma sample in order to precipitate the plasma proteins, followed by centrifugation and removal of the supernatant. This is reduced to dryness by heating under oxygen-free nitrogen, prior to reconstitution in the chromatographic mobile phase. The solution is assayed by injection on to a 5 micron particle size ODS2 analytical column, protected by a disposable RP-18 packed guard column, using an isocratic mobile phase of acetonitrile-water-isopropyl alcohol-formic acid (75:275:150:2.5, v/v). Detection is by ultraviolet absorbance at 276 nm. At a flow-rate of 1.5 ml min-1 and ambient temperature, the retention time of the drug is 16 min, whilst that for the internal standard is 21 min. This method has been validated and successfully used to assay clinical trial plasma samples. Basic pharmacokinetic parameters are presented.

The pharmacokinetics of acebutolol in man, following the oral administration of acebutolol HCl as a single dose (400 mg), and during and after repeated oral dosing (400 mg, b.d.).

The pharmacokinetics of acebutolol have been studied in eight healthy male volunteers following the oral administration of acebutolol hydrochloride ('Sectral', May & Baker) as a single dose (400 mg), and during and after repeated oral dosing (400 mg, b.d. for 56 days). Following single dose administration, considerable inter-subject variation in plasma levels of parent drug and the major metabolite, diacetolol, was evident. Acebutolol appeared to be eliminated from plasma in a bi-phasic manner, and this was confirmed from urinary excretion rate data. Mean initial and terminal half-lives of about 2 and 11 h, respectively, were determined. Plasma levels of diacetolol were greater than those of parent drug from 3 to 4 h following dose administration. Total urinary excretion of diacetolol was generally greater than that of acebutolol. During repeated dosing, steady-state plasma levels of acebutolol and diacetolol were achieved in 6 volunteers. Acebutolol did not appear to stimulate or inhibit its metabolism.

The pharmacokinetics of ketoprofen in man during and after repeated oral dosing (50 mg q.i.d.) with Orudis.

The pharmacokinetics of ketoprofen were studied in 5 healthy male volunteers after the oral administration of Orudis as a single dose (50 mg) and during, and after a 24-day repeated dosing regimen (50 mg q.i.d.). Levels of ketoprofen in plasma and urine and of conjugated ketoprofen in urine were measured after extraction, by a gas-liquid chromatographic method, which involved the use of a structurally similar internal standard. The minimum level of detection of the method was 40 ng ketoprofen/ml of plasma or 20 ng ketoprofen/ml of urine. The pharmacokinetic parameters obtained following a single oral dose, were comparable with those obtained in previous studies with human subjects from Britain, America and France. Repeated oral administration of a therapeutically effective dose of Orudis (50 mg q.i.d.), resulted in the rapid attainment of a plateau plasma level of ketoprofen, which was maintained throughout the course of dosing. Ketoprofen plasma levels and urinary clearance after the final dose of the 24-day repeated oral dosing regimen, were more variable and generally lower than those found following a single oral dose. However, the early plasma half-lives for the two experiments were similar. It was concluded that in the initial stages of repeated dosing a reduction in ketoprofen absorption, compared to that found after a single oral dose, occurred, and resulted in lower plasma levels of drug.