Pharmacokinetic and pharmacodynamic changes of furosemide after intravenous and oral administration to rats with alloxan-induced diabetes mellitus

Because some physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs to treat the disease, the pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.) and oral administration of the drug (6 mg per whole body weight) to control rats and alloxan-induced diabetes mellitus rats (AIDRs). After i.v. administration, the total body clearance (5.47 versus 7.05 mL min(-1) kg(-1)) was significantly slower in AIDRs and this was due to significantly slower renal clearance (2.35 versus 4.33 mL min(-1) kg(-1)) because the nonrenal clearance was comparable between two groups of rats. The 8 h urinary excretion of furosemide after i.v. administration decreased significantly (2280 versus 3760 mu g) in AIDRs due to impaired kidney function; the glomerular filtration rate measured by creatinine clearance was significantly slower (2.86 Versus 4.33 mL min(-1) kg(-1)) and both the plasma urea nitrogen(43.5 versus 17.3 mg dL(-1)) and kidney weight (0.953 versus 0.749% of body weight) increased significantly in AIDRs. This resulted in a significant decrease in the 8 h urine output per g kidney (17.8 versus 43.6 mL) in AIDRs. However, the 8 h diuretic efficiency was not significantly different between two groups of rats. After oral administration, the area under the plasma concentration-time curve from time 0 to 8 h decreased significantly in AIDRs (1200 versus 191 mu g . min mL(-1))due to considerably decreased absorption of furosemide from gastrointestinal tract of AIDRs. After oral administration, the 8 h urine output per g kidney (18.6 versus 36.4 mt) also decreased significantly in the AIRs due to significantly decreased 8 h urinary excretion of furosemide (405 versus 2210 mu g), however, the 8 h diuretic efficiency increased significantly (127 versus 35.2 mt mg(-1)) in AIDRs. (C) 1998 John Wiley & Sons, Ltd.