Effects of phenobarbital and 3-methylcholanthrene pretreatment on the pharmacokinetics and pharmacodynamics of furosemide in rats.
The effects of pretreatment with the enzyme inducers phenobarbital (PB) and 3-methylcholanthrene (3-MC) on the pharmacokinetic and pharmacodynamic parameters of furosemide were examined in rats. The nonrenal clearance (4.58 versus 6.18 mL/min/kg) increased significantly in PB-treated rats. This suggested that the nonrenal metabolism of furosemide increased by pretreatment with PB. This relationship was supported by the results of a tissue homogenate study; the amounts of furosemide remaining per gram of tissue after 30 min of incubation of 50 micrograms of furosemide with the 9000 x g supernatant fraction of liver, stomach, and kidney tissue homogenates decreased significantly in PB-treated rats. The contents of hepatic cytochrome P-450 (1.29 versus 2.15 nmol/mg protein) and the weights of liver and stomach increased significantly in PB-treated rats, suggesting that the metabolizing enzymes for furosemide are induced by pretreatment with PB. The 8-h urine output per 100 g of body weight increased significantly in PB-treated rats; however, the 8-h urinary excretion of furosemide per 100 g of body weight (797 versus 635 micrograms) decreased significantly in PB-treated rats. Alterations in the urine output might be due to the hormonal alterations in the concentration-effect relationship for furosemide in PB-treated rats. In 3-MC-treated rats, pharmacokinetic and pharmacodynamic parameters of furosemide were not significantly different, indicating that the metabolizing enzymes for furosemide were not induced by pretreatment with 3-MC. However, the contents of hepatic cytochrome P-450 and the weights of liver and stomach increased significantly.
Choi
Y M
YM
College of Pharmacy, Seoul National University, Korea.
Kim
S H
SH
Lee
M G
MG
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002712:Chlorides / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005665:Furosemide / Q000493:pharmacokinetics* / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D011188:Potassium / Q000652:urine; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000652:urine; D014018:Tissue Distribution
D001798:Blood Proteins; D002712:Chlorides; D008748:Methylcholanthrene; D005665:Furosemide; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; D011188:Potassium; D010634:Phenobarbital