Oral bioavailability and pharmacokinetics of DRF-4367, a new cox-2 inhibitor in rats

• Published in: European journal of drug metabolism and pharmacokinetics 2003-04, Vol.28 (2), p.137-141
• Main Authors: RAMESH, Mullangi, MAMIDI, Rao N. V. S, JAGANNATH, Kota, SUNIL KUMAR SINGH, KALLEDA SRINIVASA RAO, YELESWARAPU KOTESWAR RAO, SESHAGIRIRAO, Casturi, RAJAGOPALAN, Ramanujam, SRINIVAS, Nuggehally R
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Biological Availability; Bones, joints and connective tissue. Antiinflammatory agents; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - administration & dosage; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacokinetics; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Male; Medical sciences; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - metabolism; Pyrazoles - administration & dosage; Pyrazoles - chemistry; Pyrazoles - pharmacokinetics; Rats; Rats, Wistar; Sulfonamides - administration & dosage; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/BF03190502

The pharmacokinetic characterization of DRF-4367 (a new diaryl pyrazole derivative), a potent selective COX-2 inhibitor was performed in Wistar rats. In the first study, a single dose of 2, 5, 10, 30 or 100 mg/kg DRF-4367 was given orally to rats for investigating the dose proportionality and/or linearity in the pharmacokinetics. In the second study, a single intravenous bolus dose of DRF-4367 was given at a dose of 10 mg/kg to calculate the absolute oral bioavailability, clearance and volume of distribution parameters. Blood samples were drawn at predetermined intervals up to 24 h post-dose. The concentrations of DRF-4367 in various plasma samples were determined by a validated HPLC method. Plasma concentration versus time data was generated following oral and i.v dosing and subjected to a noncompartmental pharmacokinetic analysis. Following oral administration, maximum concentrations of DRF-4367 were achieved at about 3 h and were unchanged with incremental doses. Both Cmax and AUC0-infinity appeared to increases less than proportional to the administered oral doses. While the doses increased in the ratio of 1.0 : 2.5 : 5.0 : 15.0 : 50.0, the mean AUC0-infinity and Cmax increased in the ratios of 1.0 : 2.8 : 4.5 : 8.6 : 14.5 and 1 : 2.4 : 4.1 : 6.2 : 8.3, respectively. Following i.v. administration, the concentration of DRF4367 declined in a monoexponential fashion with terminal elimination half-life of 5.7 h. The systemic clearance and volume of distribution of DRF-4367 in rats were 0.36 L/h/Kg and 2.2 L/Kg respectively after i.v administration. Elimination half-life was unchanged with route of administration and with increase in oral doses. Absolute oral bioavailability of DRF-4367 in the efficacy dose range was 70-80%.