An HPLC method has been developed for the determination of the cephalosporin antibiotic Ro 13-9904 in plasma, urine, and bile of dogs and of human volunteers using the technique of ionpairchromatographywith a LiChrosorbRP-18 column.The three mobile phases employed contained tetrapentyl-, tetraoctyl-and hexadecyltrimethyl-ammonium bromide, respectively, as lipophilic counterions. The chromatographic conditions chosen allowed simple and rapid sample preparation. Plasma was deproteinired with ethanol and the supernatant was directly injected onto the column; urine and bile were diluted with mobile phase and injected without any purification. The detection limit for the cephalosporin was about 0.5 pg/ml for plasma samples and approximately 5 pg/ml for bile and urine.

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This study was undertaken to determine the absolute bioavailability and steady‐state concentrations of moclobemide after doses of 150 mg. In 14 healthy human volunteers, no differences in tmax, t1/2β, Cl/F, Cmax and AUC were found between a single oral dose of 100 mg and one of 150 mg. The mean absolute oral availability was 0.66 and 0.69 respectively. Plasma concentration profiles of moclobemide on repeated dosing with 150 mg 3 times daily for 15 days were essentially superimposable, although the mean concentration was higher than after the single 150 mg dose. This concentration increased over the first week and then remained relatively constant. Mean accumulation factors for moclobemide during the first week were 1.85 for Cmax and 3.0 for AUC. These values were higher than predicted from single‐dose characteristics. There was a marked reduction in the variability of AUC and clearance (CI/F) values at steady‐state compared with the first dose. Minimum plasma concentrations of the 2 metabolites, Ro 12‐5637 and Ro 12‐8095, were relatively stable throughout dosing. The exact mechanism of the decrease in systemic and oral clearance of moclobemide with time during multiple oral dosing is not known at present. Either moclobemide inhibits its own clearance or moclobemide metabolism is inhibited by one or more of its metabolites. The findings indicate that, if dosage needs to be adjusted during treatment with moclobemide, the changes should be made carefully and at intervals of not less than 1 week.

Eight patients were given flunitrazepam 2 mg orally, once daily for 28 consecutive days. The time-course of the plasma concentration of unchanged flunitrazepam and its principal metabolites were studied in detail after the first and last doses. Additional blood samples were collected immediately before administration of the tablet on days 4, 7, 11, 14, 18, 21 and 25. Clinically there were not changes during the trial period in the onset of sleep, duration of sleep, depth of sleep measured as number of spontaneous awakenings, or in the patients' condition on awakening. The time-course of the plasma concentration of flunitrazepam could be described by a three-compartment model, assuming that the rate constants remained unchanged during treatment. Maximal plasma concentrations of unchanged flunitrazepam, found two hours after intake, reached 10-15 ng/ml after the first and 15-20 ng/ml after the last dose. The beta-half-life was found to be between 20 and 36 h.

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