Pharmacodynamic and pharmacokinetic evaluation of CS-526 in cynomolgus monkeys
| Autor: | Shibakawa Nobuhiko, Keiichi Ito, Fumi Inaba, Yuka Morikawa-Inomata, Keiichi Tabata, Atsuyuki Tomizawa, Kazuya Kinoshita, Naotoshi Yamamura |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Time Factors Metabolite Pharmaceutical Science Administration Oral Biological Availability Pharmacology Gastric Acid chemistry.chemical_compound Pharmacokinetics Oral administration Animals Pyrroles Gastric Acidity Determination Cross-Over Studies Dose-Response Relationship Drug Stomach Antagonist General Medicine Hydrogen-Ion Concentration Crossover study Pyridazines Dose–response relationship Macaca fascicularis chemistry Gastric Mucosa Pharmacodynamics Area Under Curve Injections Intravenous |
| Zdroj: | Biologicalpharmaceutical bulletin. 32(12) |
| ISSN: | 1347-5215 |
| Popis: | In the present study, we evaluated the effect of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) on the intragastric acidity of cynomolgus monkeys. The study was performed in a crossover manner with five male animals. CS-526 was administered orally or intravenously at doses of 3.0, 10 and 30 mg/kg, or 0.3, 1.0 and 3.0 mg/kg, respectively. The time period in which the intragastric pH was 4.0 or more (Time(pH > or = 4.0)) and the median pH were calculated for 24 h after the administration. The intragastric pH was elevated after CS-526 treatment. The Time(pH > or = 4.0) was increased in a dose-dependent manner (p = 0.0292) in the oral administration, and the median pH was also increased in a dose-dependent fashion (p = 0.0491) in the intravenous administration. The plasma concentration of CS-526 and its metabolite R-130185 was increased after oral and intravenous administration of CS-526, except for one animal which did not show any detectable amount of R-130185 after intravenous administration at the lowest dose. The area under the time-concentration curve of the active component was increased in the dose proportional manner after oral and intravenous administration. The absolute bioavailability of the active component was estimated to be approximately 1%. Correlation between the pharmacodynamic parameters and the pharmacokinetic parameters was observed in oral (p = 0.0029-0.0745), but not in intravenous administration (p = 0.0558-0.2789). In conclusion, oral and intravenous administration of CS-526 showed inhibition on gastric acidity in cynomolgus monkeys using intragastric pH-metry and some pharmacokinetic and pharmacodynamic parameters were well correlated. |
| Databáze: | OpenAIRE |
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