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The effect of sleep on quazepam kinetics was studied in 12 normal adult men. In a randomized two-way crossover design, each subject received one 15-mg quazepam tablet either at night just before sleep or in the morning after a night's sleep. Blood samples were drawn before and at specified times (to 120 hr) after dosing. To assure that blood collection did not interfere with sleep, blood was drawn by an indwelling catheter from a large arm vein. Plasma concentrations of quazepam and its two major plasma metabolites (which are also active) 2-oxoquazepam and N-desalkyl-2-oxoquazepam (N-desalkylflurazepam) were determined by specific GLC methods. Kinetic analysis was by a two-compartment open model with first-order absorption/formation kinetics. Quazepam was rapidly absorbed with both administration times; absorption t 1/2 was 0.7 to 0.9 hr. Absorption lag time was slightly longer after the nighttime dose (1.0 and 0.6 hr). Maximum concentration and AUC of quazepam and 2-oxoquazepam and AUC of N-desalkyl-2-oxoquazepam were somewhat higher after nighttime dosing, most likely a result of decreased apparent volume of distribution of the central compartment after the nighttime dose (5.0 l/kg for nighttime dosing and 8.6 l/kg for morning dosing). The elimination t 1/2s of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam after the morning dose were 25, 28, and 79 hr, which did not differ from those values after the nighttime dose. In general, time of dosing had no appreciable effect on quazepam kinetics or those of its major active plasma metabolites. The small differences between the two dose times are not expected to have clinical significance.

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The pharmacokinetics of rosaramicin was studied in subjects receiving 500 mg of the drug (i) by 1-h intravenous infusion, (ii) in solution orally, or (iii) as tablets orally. After intravenous administration, the rosaramicin levels in serum declined rapidly with t112S of 0.27 h for the distribution phase and 3.28 h for the elimination phase. The apparent volume of distribution was 3.78 liter/kg, and the total body clearance was 13.41 ml/min per kg, indicating extensive tissue distribution or metabolism or both. Similar pharmacokinetic data were obtained after oral administration of the drug in solution or tablets and after intravenous dosing. The absolute bioavailability of the drug administered orally, in either tablets or solution, was 32 to 39%. The metabolism and excretion of [14C]rosaramicin administered orally were also evaluated in volunteers. The serum area under the curve (oo) of unchanged rosaramicin was 19% of that of total radioactivity, indicating extensive metabolism of the drug. About 7.0% of the radioactivity was recovered in the urine, and 86.7% was recovered in the feces. Only a small amount of unchanged rosaramicin was present in the urine (7 to 9% of urinary radioactivity), but none was present in the feces. The major metabolite, 20-bis-ureidorosaramicin, represented 17 to 38% of the radioactivity in the urine and 26 to 29% of the radioactivity in the feces.Rosaramicin is a broad-spectrum macrolide antibiotic, similar to erythromycin (1, 10). The antibiotic is isolated from fermentation broth of Micromonospora rosaria (11). Rosaramicin has been shown to have good in vitro activity against gram-positive aerobes and anaerobes. In addition, rosaramicin has been shown to have greater in vitro activity than erythromycin against a variety of gram-negative organisms and anaerobes, including Bacteroides and Mvcoplasma species (12). This paper describes the pharmacokinetics of rosaramicin in subjects receiving 500-mg doses by (i) 1-h intravenous infusion, (ii) solution orally, or (iii) tablets orally. The metabolism and excretion of ['4C]rosaramicin after oral administration of a 500-mg dose of [14C]rosaramicin were also evaluated. MATERIALS AND METHODSCompound. For the pharmacokinetic study, a rosaramicin solution (100 mg/ml) for oral administration was obtained by adding 3 ml of sterile water to the sterile vial containing rosaramicin sodium dihydrogen phosphate, lyophilized powder (equivalent to 300 mg of rosaramicin base). The rosaramicin solution (2.5 mg/ml) for intravenous infusion was obtained by adding 12 ml of the oral solution to 468 ml of saline. The 250-mg rosaramicin tablets were manufactured by Schering Corp.For the metabolic study, 5-[14C]rosaramicin (Fig. 1) inverse isotope dilution technique and high-pressure liquid chromatography (HPLC), was greater than 95%.Administration of rosaramicin. Twelve healthy male volunteers participated in the pharmacokinetic study of single blind three-way crossover design. After an 8-h fast, each subject received 500 mg of rosaramicin as (i) two 250-mg...

Pharmacokinetic parameters of Sch 34343 have been determined for mice, rats, rabbits, monkeys, dogs and humans and correlated among species as an exponential function of body weight. The pertinent pharmacokinetic parameters tested are apparent and steady-state volumes of distribution, total body clearance, elimination phase half-life, and mean residence time. This study showed that the extrapolation of animal data to humans on a new investigational drug, Sch 34343, can be potentially useful.