Colin McMartin

Disposition of glutethimide in man.

The disposition of glutethimide in man was studied by measurement of drug concentrations in plasma, whole blood, urine, and breast milk after oral doses. In vitro, plasma protein binding and ionization constants were measured. Wide variations in absorption of the drug were observed, the peak plasma concentration varying from 2.85 to 7.05 μg per milliliter and occurring at any time from one to 6 hours after administration of 500 mg. doses. Decline of the concentration after the peak lwd been reached occurred in one phase in 2 subjects and in two phases in 4 subjects. The earlier of the two phases was the one of more rapid decline. Higher concentrations were recorded after the higher of two doses (250 and 500 mg.). Concentrations in whole blood and plasma were similar and an average of 54.2 per cent of the plasma content of the drug was bound to protein in vitro. Concentrations in urine were lower than those in plasma, and it was estimated thot less than 2 per cent of a dose was excreted as unchanged drug in 24 hours by this route. Mean concentrations of the drug in breast milk were also very low. Maternal and neonatal plasma concentrations of the drug were similar. These fondings were examined in relation to other observations of glutethimide kinetics, to treatment of patients with glutethimide poisoning, and to duration and intensity of central depressant effects.

The absorption and metabolism of guanethidine in hypertensive patients requiring different doses of the drug

To find out whether difJerences in absorption and metabolism are responsible for the Zarge variation in dose requirement of guanethidine, the quantities of the drug and its metabolites exereted in the urine were measured with the use of a chromatographie method for the separation and quantitative assay of basic drugs in urine. All patients were found to excrete unehanged drug and two metabolites. The percentage of the dose absorbed varied from 3 to 27 per cent, but this was not the only factor determining dose requirement of the drug because the absolute amount of drug absorbed also varied eonsiderably (6.4 to 30 mg. per day).

The specific assay of basic drugs in urine by cm-cellulose chromatography using continuous drug—dye complex extraction as a detection system

Abstract An automated assay procedure suitable for detecting basic compounds in the eluate from CM-cellulose columns is described. Using this procedure the behaviour on CM-cellulose columns of a number of drugs and of naturally occurring interfering compounds in human urine was investigated. It was found that the drugs could be eluted as sharp symmetrical peaks which in most cases could be resolved from interfering urinary components by suitable choice of the pH of the buffer used for elution. Chromatograms obtained from cyclizine, pethidine and amphetamine at 1 μg/ml and morphine at 2 μg/ml in urine showed that these drugs could readily be resolved from urinary components at this concentration. The resolution of guanethidine and its metabolites required the successive use of two buffers for elution. Quantitative aspects of the method were investigated for guanethidine and its metabolites, and a linear relationship was obtained between the peak area due to each of these compounds and the amount added to drug-free urine in the range of 1–20 μg/ml.

The preparation of high resolution microgranular carboxymethyl cellulose columns and their application to the separation of guanethidine and its metabolites in urine

Abstract Colunms (1.2 × 6 cm) with up to 100 theoretical plates/cm were prepared using CM cellulose which had been graded by back-washing. The columns were fitted with specially made polythene column ends to allow samples to enter and leave the column bed with minimum distortion and were rapidly packed at high flow rates of buffer. The columns could be operated at low pressures and used repeatedly over several weeks. Four columns connected in series were used to separate radioactive products excreted in the urine of rats which had been treated with guanethidine. Four radio-active products which accounted for 99% of the applied radioactivity were identified as 1-(6.carboxyhexyl)-2-iminoimidazolidine, 2.(6-carboxyhexylamino)-ethylguanidine, guanethidine N-oxide and guanethidine.