Summary
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-∞ 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-∞ 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 DRF-4367 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%.
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References
Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L Isakson P. (1994): Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA; 91: 12013–12017.
David L De Witt (1999): COX-2 selective inhibitors: The new super aspirins. Mol Pharmacol; 4: 625–631.
Amit SK, Zhiyang Zhao (2001): Discovery and design of selective cyclooxygenase-2 inhibitors as non-ulcerogenic, anti-inflammaotry drugs with potential utility as anti cancer agents. Current Drug Targets; 2: 79–106.
Jackson, L. M.; Hawkey, C. J. (1999): Gastrointestinal effects of COX-2 Inhibitors. Expert Opin. Invest. Drugs, 8, 963–971.
Scrip 2000, 2554, 20.
Steinbach G, Lynch PM, Phillips R K, Wallace MH, Hawk E, Gordon GB, Wakabyashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B. (2000): The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. New Eng J Med; 342: 1946–1952.
For a review, see: Dannhardt, G.; Kiefer, W. (2001): Cyclooxygenase inhibitors — Current status and future prospects. Eur. J. Med. Chem., 36, 109–126.
Sunil et al. (2002): Design, Synthesis and Biological Evaluation of 2-Substituted Benzene sulphonamide Containing Novel Class of 1,5-Diaryl Pyrazoles as Cyclooxy-genase-2 Inhibitors. J. Med. Chem. submitted.
R Mullangi et al.: Validated HPLC method for determination of DRF-4367, a novel COX-2 inhibitor, in rat plasma. J. Pharm. Biomed. App. (in preparation).
Gibaldi M. and Perrier D. (1982): Pharmacokinetics2nd edn, New York: Marcel Dekker, pp. 409–417.
Rao N.V.S. Mamidi, Ramesh Mullangi, Jagannath K., Ansar A.K. et al. (2002): Pharmacological and pharmacokinetic evaluation of celecoxib prodrugs in rats. Biopharmaceutics and Drug Disposition., 23, 7, 273–282.
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Ramesh, M., Mamidi, R.N.V.S., Jagannath, K. et al. Oral bioavailability and pharmacokinetics of DRF-4367, a new cox-2 inhibitor in rats. Eur. J. Drug Metab. Pharmacokinet. 28, 137–141 (2003). https://doi.org/10.1007/BF03190502
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DOI: https://doi.org/10.1007/BF03190502