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.
Kim
S H
SH
College of Pharmacy, Seoul National University, Korea.
Park
K J
KJ
Yoon
W H
WH
Lee
J W
JW
Kim
N D
ND
Lee
M G
MG
D000818:Animals; D019540:Area Under Curve; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D004232:Diuretics / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005665:Furosemide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013424:Sulfanilamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000494:pharmacology*; D013777:Tetrazoles; D013876:Thiophenes; D000096926:Benzenesulfonamides
D004232:Diuretics; D005665:Furosemide; D013424:Sulfanilamides; D013844:Thiazoles; C098009:YH 439; C018222:azosemide; D013777:Tetrazoles; D013876:Thiophenes; D000096926:Benzenesulfonamides