Pharmacokinetics of the investigational cephalosporin ceftriaxone were studied after 30-min intravenous infusions of three ascending single doses of 0.5, 1, and 2 g crossed over in 12 normal subjects. Serially collected plasma and urine samples were analyzed for ceftriaxone by high-performance liquid chromatography. Plasma concentration-time profiles were characterized by a linear two-compartment open model with the following respective mean (+standard deviation) parameters at 0.5-, 1-, and 2-g dose levels: elimination half-life, 6.5 + 0.7, 6.2 + 0.8, and 5.9 ± 0.7 h; apparent volume of distribution, 8.5 + 1.1, 9.0 + 1.1, and 10.1 ± 1.0 liters; and plasma clearance, 929 ± 150, 1,007 ± 130, and 1,190 ± 150 ml/h. The respective renal excretion parameters were as follows: renal clearance, 373 ± 60, 399 ± 50, and 533 + 128 ml/h; and percentage of dose excreted unchanged in the 48-h urine samples, 41 ± 8, 39 ± 5, and 43 + 10. The 6-h elimination halflife of ceftriaxone was 2-to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explained by the concentration-dependent plasma protein binding of ceftriaxone in humans.

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proach to ac polarography in the harmonic multiplex mode because it replaces numerous analog circuits, which require tuning, offset adjusts, etc., by a drift-free, highly automated digital program. On the other hand, because it places minimal demands on data acquisition capability, an analog conditioning approach such as the one used in this work is favored whenever digital data acquisition rates are too slow to meet the demands of digital signal conditioning-e.g., whenever one has to operate with a slob dedicated minicomputer system, or with a low-priority time shared terminal to a large computer or when applied signals of very high frequency are employed. ACKNOWLEDGMENTThe authors are indebted to Barry J. Huebert for helpful discussions and programming assistance.A sensitive and specific differential pulse polarographic assay was developed for the determination of glibornuride (a tolylsulfonylurea hypoglycemic a ent) in blood. It involves the selective extraction 09 the compound from whole blood into diethyl ether and back-extraction into 1. ON ",OH.Following suitable "clean-up" of the sample, the compound is nitrated in 10% KNOa/H2S04 at 105 O C for 2 hours. The nitro derivative is extracted into ethyl acetate, the residue is dissolved in 0.1N NaOH, deoxygenated, and analyzed by differential pulse polarography. The overall recovery of the assay is 80.7% i 8.0 (Std dev) from blood and the sensitivity limit is 0.05-0.10 pg/ml of blood (using a 2-ml sample per assay). The method was applied to the determination of blood levels of the intact drug in man following single oral doses of 50 and 100 mg of glibornuride.

Following administration of chlordiazepoxide HCl to man, N-desmethyldiazepam, a known metabolite of diazepam (Valium), was identified in plasma. The metabolite was identified on the basis of its thin-layer chromatographic (TLC) mobility, electron-capture gas-chromatographic (EC-GC) retention time, and mass spectrum relative to authentic N-desmethyldiazepam. Plasma levels of N-desmethyldiazepam in subjects receiving both single and chronic doses of chlordiazepoxide were determined by an EC-GC method with a limit of sensitivity of 10 ng/ml using 2-ml samples and by a radioimmunoassay procedure which had a limit of sensitivity of 20 ng/ml using a 0.1-ml sample. Both assay methods gave good agreement for the levels of N-desmethyldiazepam. In subjects receiving a single 30-mg oral or intravenous dose of chlordiazepoxide, measurable levels of N-desmethyldiazepam in plasma (10 to 60 ng/ml) were obtained 24 to 72 hr after administration. In 5 subjects receiving 10 mg of chlordiazepoxide three times a day, steady-state levels of N-desmethyldiazepam in plasma were reached after about 1 wk of administration. The mean maximum and minimum steady-state levels of N-desmethyldiazepam were 260 and 220 ng/ml of plasma, respectively. Similar steady-state levels were observed on treatment with 30 mg of chlordiazepoxide over 24 hr.