Pharmacokinetics and pharmacodynamics of intravenous torasemide in diabetic rats induced by alloxan or streptozotocin.
The pharmacokinetic and pharmacodynamic parameters of torasemide were compared after intravenous administration at a dose of 2 mg/kg to diabetic rats induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. It was reported that torasemide was mainly metabolized via CYP2C11 in rats and the expression and mRNA level of CYP2C11 decreased in DMIA and DMIS rats. Hence, it could be expected that the time-averaged nonrenal clearance (Cl(nr)) of torasemide could be slower in the diabetic rats. As expected, the Cl(nr) values were significantly slower in DMIA (0.983 versus 1.35 ml/min/kg) and DMIS (0.998 versus 1.36 ml/min/kg) rats. However, the time-averaged renal clearance (Cl(r)) values of torasemide were significantly faster in DMIA (0.164 versus 0.0846 ml/min/kg) and DMIS (0.205 versus 0.0967 ml/min/kg) rats due to urine flow rate-dependent timed-interval Cl(r) of torasemide in rats. The comparable time-averaged total body clearance (Cl) values between the diabetic and control rats were due to partially compensated Cl(r) in the diabetic rats. The 8 h urine output and diuretic efficiency increased significantly in the diabetic rats due to significantly greater 8 h urinary excretion of unchanged torasemide and at least partly due to an increase in urine output in diabetes per se (without administration of any drugs).
Kim
Yu C
YC
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Republic of Korea.
Oh
Eun Y
EY
Kim
So H
SH
Lee
Myung G
MG
D000496:Alloxan; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D039181:Steroid 16-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D013311:Streptozocin; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077786:Torsemide
D012333:RNA, Messenger; D049994:Sodium Potassium Chloride Symporter Inhibitors; D013449:Sulfonamides; D013311:Streptozocin; D000496:Alloxan; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D000077786:Torsemide