Pharmacokinetics and pharmacodynamics of furosemide after intravenous and oral administration to spontaneously hypertensive rats and DOCA‐salt‐induced hypertensive rats

The pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.), 1 mg/100 g body weight, and oral administration, 2 mg per 100g body weight, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate‐salt‐induced hypertensive rats (DOCA‐salt rats). After i.v. administration, the 8 h urinary excretion of furosemide/g kidney (397 versus 572 μg) was significantly lower and the non‐renal clearance (5.78 versus 3·94 ml min−1 kg−1) was significantly faster in SHRs of 16 weeks of age than in age‐matched control Wistar rats. This suggested that the nonrenal metabolism of furosemide could be faster in SHRs of 16 weeks of age than in age‐matched control Wistar rats, and this could be supported by the significantly greater amount of 4‐chloro‐5‐sulphamoyl anthranilic acid, a metabolite of furosemide, excreted in 8 h urine as expressed in terms of furosemide (11·1 versus 4·79% of the i.v. dose) in SHRs. It could also be supported at least in part by a study of liver homogenate; the amount of furosemide remaining per gram of liver after 30 min incubation of 50μg of furosemide with the 9000g supernatant fraction of liver homogenate was significantly smaller (40·4 versus 43·7μg) in SHRs of 16 weeks of age than in age‐matched Wistar rats. The greater metabolic activity of furosemide in liver may also be supported by the result that the amount of hepatic cytochrome P‐450 (0·7013 versus 0·5186 nmol/mg protein) and the weights of liver (3·52 versus 2·93% of body weight) were significantly greater in SHRs of 16 weeks of age than in age‐matched Wistar rats. After i.v. administration of furosemide, the 8 h urine output (9·93 versus 16·5 ml) and 8 h urinary excretion of sodium (1·21 versus 2·05 mmol) and chloride (1·37 versus 2·17 mmol) per gram of kidney in SHRs of 16 weeks of age were lower than those in age‐matched Wistar rats, this could be due to the significantly smaller amount of furosemide excreted in 8 h urine per gram of kidney. After oral administration, the pharmacokinetics and pharmacodynamics of furosemide were not significantly different between SHRs and the control Wistar rats of 16 weeks of age. After i.v. and oral administration of furosemide, there were no significant differences in the pharmacokinetics and pharmacodynamics between DOCA‐salt rats and control SD rats of 16 weeks of age except for the significantly lower urinary excretion of potassium per gram of kidney in DOCA‐salt rats. On the other hand, the 8 h urinary excretion of furosemide and non‐renal clearance were not significantly different between SHRs of six weeks of age and age‐matched control Wistar rats after i.v. administration of furosemide. Since the non‐renal metabolism of furosemide was not faster in either DOCA‐salt rats of 16 weeks of age or SHRs of six weeks of age than that in the respective age‐matched control group, the faster non‐renal metabolism of furosemide in SHRs of 16 weeks of age could be due to the physiological factor from the chronic phase of hypertension in SHRs, and could not be due solely to the heredity of SHRs or the hypertensive state itself.