Formulation dependent pharmacokinetics, bioavailability and renal toxicity of a selective cyclooxygenase-1 inhibitor SC-560 in the rat.

Purpose: To delineate formulation dependent pharmacokinetics and bioavailability of SC-560, a relatively new cycloooxygenase-1 (COX-1) specific inhibitor, in the rat and examine its influence on the renal tubular enzyme, N-acetyl-beta-D-glucosaminidase (NAG), and urinary electrolytes.

Methods: The pharmacokinetics of SC-560 was studied in Sprague-Dawley rats (n = 5 per group) after a single intravenous (i.v.) and oral dose (10 mg/kg) in polyethylene glycol (PEG) 600 and a single oral dose (10 mg/kg) in 1% methylcellulose (MC). Serial blood samples were collected via a catheter inserted in the right jugular vein and serum samples were analysed for SC-560 using reverse phase HPLC. After oral administration of SC-560 in PEG, urine was also collected for 24 h and analysed for urinary sodium, chloride, and potassium as well as NAG.

Results: After an iv dose (10 mg/kg) of SC-560, serum AUC, t(1/2), CL and Vd were 9704 +/- 4038 ng h/mL, 5.4 +/- 0.8 h, 1.15 +/- 0.46 L/h/kg and 9.1 +/- 4.6 L/kg (mean +/- SD, n = 5), respectively. Oral administration of 10 mg/kg SC-560-PEG and MC (n=5 rats) yielded serum AUC, C max, t (max )and t (1/2) of 1203.4 +/- 130.3 and 523 +/- 208 ng h/mL, 218.5 +/- 86.9 and 119.8 +/- 15.5 ng/mL, 1.00 +/- 1.8 and 2.0+/- 0 h, 3.7 +/- 1.6 and 2.7 +/- 1.7 h (mean +/- SD, n = 5), respectively. A single oral dose 10 mg/kg of SC-560 in PEG resulted in an increase in NAG excretion in urine and a reduction in 0-24 h urinary sodium, potassium, and chloride excretion.

Conclusions: SC-560 extensively distributes into rat tissues, and has a CL approaching hepatic plasma flow. The drug displays low <15% and formulation dependent bioavailability after oral administration and demonstrates kidney toxicity.