Pharmacokinetic profile and in vitro selective cyclooxygenase-2 inhibition by nimesulide in the dog
Autor: | T. Haak, S. Metge, C. C. Cester, Pierre-Louis Toutain |
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Rok vydání: | 2001 |
Předmět: |
Male
Administration Oral Biological Availability Pharmacology Injections Intramuscular Dogs Pharmacokinetics Oral administration medicine Animals Potency Cyclooxygenase Inhibitors IC50 Whole blood Volume of distribution Sulfonamides Cyclooxygenase 2 Inhibitors Dose-Response Relationship Drug General Veterinary Chemistry Anti-Inflammatory Agents Non-Steroidal Bioavailability Isoenzymes Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Injections Intravenous Nimesulide medicine.drug |
Zdroj: | Journal of Veterinary Pharmacology and Therapeutics. 24:35-42 |
ISSN: | 1365-2885 0140-7783 |
DOI: | 10.1046/j.1365-2885.2001.00303.x |
Popis: | The pharmacokinetic properties and in vitro potency of nimesulide, a nonsteroidal anti-inflammatory drug (NSAID) were investigated in 8 or 10 dogs after intravenous (i.v.), intramuscular (i.m.) and oral (single and multiple dose) administrations at the nominal dose of 5 mg/kg. After i.v. administration, the plasma clearance was 15.3 +/- 4.2 mL/kg/h, the steady-state volume of distribution was low (0.18 +/- 0.011 L/kg) and the elimination half-life was 8.5 +/- 2.1 h. After i.m. administration, the terminal half-life was 14.0 +/- 5.3 h indicating a slow process of absorption with a maximum plasma concentration (6.1 +/- 1.5 microg/mL) at 10.9 +/- 2.1 h postadministration and the systemic bioavailability was 69 +/- 22%. After oral administration in fasted dogs, the maximal plasma concentration (10.1 +/- 2.7 microg/mL) was observed 6.1 +/- 1.6 h after drug administration, the plasma half-life was 6.2 +/- 1.9 h and the mean bioavailability was 47 +/- 12%. After daily oral administrations for 5 days, the average plasma concentration during the fifth dosage interval was 8.1 +/- 2.9 microg/mL and the overall bioavailability was 58 +/- 16%. The mean accumulation ratio was 1.27 +/- 0.4. In vitro nimesulide inhibitory potencies for cyclooxygenase (COX)-1 and COX-2 isoenzymes were determined using a whole blood assay. Canine clotting blood was used to test for inhibition of COX-1 activity and whole blood stimulated by lipopolysaccharide (LPS) was used to test for inhibition of COX-2 activity. The inhibitory concentration (IC50) for inhibition of COX-2 and COX-1 were 1.6 +/- 0.4 microM (0.49 +/- 0.12 microg/mL) and 20.3 +/- 2.8 microM (6.3 +/- 0.86 microg/mL) giving a nimesulide COX-1/COX-2 ratio of 12.99 +/- 3.41. It was concluded that at the currently recommended dosage regimen (5 mg/kg), the plasma concentration totally inhibits COX-2 and partly inhibits COX-1 isoenzyme. |
Databáze: | OpenAIRE |
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