Pharmacokinetics and Safety of Ascending Single Doses of DZ-2640, a New Oral Carbapenem Antibiotic, Administered to Healthy Japanese Subjects
| Autor: | Yoichi Murakami, Kenichi Sato, Hideo Hakusui, Kinuyo Kato, Makoto Tanaka, Yasushi Ito, Keiji Kawamoto |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Male
Pharmacology Chemistry Cmax Blood Proteins Urine Bioavailability Infectious Diseases Carbapenems Double-Blind Method Japan Pharmacokinetics Oral administration Blood plasma Humans Biological Assay Pharmacology (medical) Chromatography High Pressure Liquid Active metabolite Protein Binding Antibacterial agent |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 44:578-582 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.44.3.578-582.2000 |
| Popis: | DZ-2640 is the ester-type oral carbapenem prodrug of an active parent compound, DU-6681. The pharmacokinetics and safety of DU-6681 were investigated in six studies after oral administration of a single dose of DZ-2640 to healthy male Japanese volunteers at doses of 25, 50, 100, 200, and 400 mg (as the equivalents of DU-6681) in the fasted state. The same volunteers received the drug at a dose of 100 mg in the fasted and fed states to examine the effect of food intake on the bioavailability of DZ-2640. The concentrations of DU-6681 in plasma and urine were determined by a validated high-performance liquid chromatography method and a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of DU-6681 in plasma ( C max ) ranged from 0.263 μg/ml (25-mg dose) to 2.489 μg/ml (400-mg dose) and were reached within 1.5 h following drug administration. After reaching the C max , plasma DU-6681 concentrations declined in a monophasic manner, with a half-life of 0.47 to 0.89 h. The area under the concentration-time curve (AUC) and C max increased almost linearly with the dose up to the 200-mg dose. The AUC and C max increased less than proportionally after administration of the 400-mg dose, suggesting a reduction in drug absorption. The plasma protein binding of DU-6681 was in the range of 23.3 to 25.6%. The cumulative urinary recoveries (0 to 24 h) were in the range of 31.9 to 44.9%. The AUC was slightly but statistically significantly reduced by food intake. However, the C max , half-life, and recovery in urine were not affected by food intake. The renal clearance (402 to 510 ml/min) was much greater than the mean glomerular filtration rate (ca. 120 ml/min), which indicated active tubular secretion of the drug. A mild transient and moderate diarrhea was observed in two of six volunteers in the study with a single dose of 25 mg. Mild soft stools were observed in two of six volunteers who received a 400-mg dose of the drug. |
| Databáze: | OpenAIRE |
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