Effect of a hepatoprotective agent, YH-439, on the pharmacokinetics of furosemide and azosemide in rats.

The effect of YH-439 pretreatment on the pharmacokinetics of furosemide and azosemide was investigated after intravenous (iv) administration of furosemide, 6 mg per whole body weight, and azosemide, 10 mg per kg body weight, to rats pretreated with 3 consecutive daily oral administration of YH-439, 200 mg per kg body weight. The nonrenal clearance of furosemide (2.20 versus 3.53 ml/min/kg) increased significantly, and the 24 h-urinary excretion of furosemide (both the amount and percentages of iv dose) decreased significantly in the YH-439 treated rats when compared with those in the control rats. The results were unexpected since the metabolism of furosemide increased by pretreatment with phenobarbital (CYP2B inducer) and YH-439 pretreatment failed to affect CYP2B expression. The increased metabolism of furosemide by pretreatment with YH-439 could be due to other enzyme(s) induced by pretreatment with YH-439. Pharmacokinetic parameters of azosemide were not significantly different between the two groups of rats except t(1/2), MRT, and V(ss). The results were unexpected since azosemide metabolism increased with 3-methylchloranthane (3-MC, CYP1A inducer) and YH-439 pretreatment increased CYP1A expression. Above data indicate that the expression of CYP1A by treatment with YH-439 was not considerable when compared with that with 3-MC.