Determination of efficacy of linotroban by inducing a reduction of renal inulin/para-aminohippuric acid clearances with the thromboxane A2 mimetic U-46619 in the conscious female rat.

Linotroban (CAS 141443-73-4), a potent and selective thromboxane (TXA2) receptor antagonist, is known as a novel antithrombotic agent. It is suggested that pharmacological inhibition of TXA2 synthesis or action merits continued evaluation in the treatment of a variety of renal diseases. The aim of this study was the determination of efficacy of this new TXA2 receptor antagonist by assessing its effect on the reduction in inulin and para-aminohippuric acid (PAH) clearances induced by the TX/prostaglandin endoperoxide mimetic U-46619 in the conscious female rats. The following doses (3, 10, 30 mg/kg/24 h) of linotroban mixed with 720 micrograms TX-mimetic U-46619/kg/24 h were administered via osmotic pumps at a delivery rate of 10 microliters/h, implanted s.c. during 72 h. Rats of the U-46619 group were administered 720 micrograms U-46619/kg/24 h alone as described above, controls received 3.5% NaHCO3, respectively. Inulin/PAH clearances were determined at the end of the 4-h clearance period (68 h-72 h). Summarizing the data, glomerular filtration rate (GFR) and PAH clearances were reduced significantly by U-46619. When linotroban (3, 10 or 30 mg/kg/24 h) was added to U-46619 the GFR and PAH clearance were reversed to values that showed no significant differences to the controls.