| In Vitro | In vitro activity: Valdecoxib inhibits LPS-induced PGE2 production in plasma with IC50 of 0.89 μM for assessment of the extent of COX-2 inhibition. Valdecoxib inhibits TxB2 production in plasma with IC50 of 25.4 μM for assessment of the extent of COX-1 inhibition. Valdecoxib binds to COX-2 with Ka of 1.1×105 M/s. The overall saturation binding affinity for COX-2 of Valdecoxib is 2.6 nM. Valdecoxib shows similar activity in the human whole-blood COX assay (COX-2 IC50 = 0.24 μM; COX-1 IC50 = 21.9 μM). The affinity of [3H]Valdecoxib for COX-2 with KD of 3.2 nM. The binding of Valdecoxib to COX-2 seems to be both rapid and slowly reversible with association rates of 4.5 × 106/M/min and dissociation rates of 7.0 × 10-3/min (t1/2 of 98 min). The percent of dissolved Valdecoxib at 15 min (DP15) is 10.5% for Valdecoxib and 50%, 91% and 93% for its hydrophilic derivatives (VALD-βCd, VALD-HPβCd and VALD-SBE7βCd complexes), respectively.
Cell Assasy: HMEC-1 cells proliferation is measured using the MTT conversion method. Cells are seeded (50.000 cells/well) into 96-well plates. The cells are incubated for 24 h with LPS 100 μg/mL, CoCl2 200 μM, Valdecoxib 10 or 100 μM, LPS and Valdecoxib or CoCl2 and Valdecoxib or without tested chemicals (control group). All the substances are added at the same time. After incubation, 50 μL MTT (1 mg/mL) is added and the plates are incubated at 37°C for 4 h. At the end of the experiment, cells are exposed to 100 μL DMSO, which enables the release of the blue reaction product-formazan. The absorbance at 570 nm is read on a microplate reader and results are expressed as a percentage of the absorbance measured in control cells
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In Vivo | Valdecoxib administrated orally inhibits rat carrageenan foot pad edema with ED50 of 10.2 mg/kg. Valdecoxib administrated orally shows chronic antiinflammatory activity with ED50 of 0.032 mg/kg/day in rat adjuvant arthritis model. Valdecoxib administrated orally shows blockade of prostaglandin production at the inflammatory site with ED50 of 0.02 mg/kg in the rat carrageenan air pouch model. Valdecoxib demonstrates marked potency in acute and chronic models of inflammation (air pouch ED50 = 0.06 mg/kg; paw edema ED50 = 5.9 mg/kg; adjuvant arthritis ED50 = 0.03 mg/kg) in rats. Valdecoxib alone shows slow in vivo absorption giving maximum % inhibition of edema (16%) after a period of 3 hour. In contrast, VALD-βCd and VALD-SBE7βCd complexes shows high absorption rate in vivo achieving more than 50% inhibition of edema in the 1 hour and maximum percentage of inhibition of edema (66%) after a period of 3 hours. Valdecoxib (5 mg/kg, po) results in AUC in plasma of 3.58 μg*h/mL and 2.08 μg*h/mL in males and female mice, respectively. Valdecoxib (5 mg/kg, po) results in AUC red blood cells of 12.1 μg*h/mL and 6.42 μg*h/mL in males and female mice, respectively. |
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