Pharmacokinetics and pharmacodynamics of intravenous torasemide in diabetic rats induced by alloxan or streptozotocin

Abstract

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).

Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus

“…Torasemide CYP2C11 in rats Significantly slower and comparable intravenous CL NR values of torasemide in DMIA and DMIS rats, respectively [111] Significantly larger 8-h urine output after the intravenous administration to DMIA and DMIS rats [111] 10…”

“…[109,110] After the intravenous administration of 2 mg/kg torasemide to male Sprague-Dawley DMIA rats on the fourth day, the CL NR (which could have represented their metabolic clearance) became significantly slower (by 27.2%) than that of the controls. [111] This could have been at least partly due to the significantly smaller free fractions of torasemide in the plasma from DMIA rats (3.56 vs 9.57%). [111] The hepatic CL int for the disappearance of torasemide was not measured because torasemide is a drug with a low hepatic extraction ratio in rats (its 'direct' hepatic first-pass effect was found to be 3-4%).…”

“…[111] This could have been at least partly due to the significantly smaller free fractions of torasemide in the plasma from DMIA rats (3.56 vs 9.57%). [111] The hepatic CL int for the disappearance of torasemide was not measured because torasemide is a drug with a low hepatic extraction ratio in rats (its 'direct' hepatic first-pass effect was found to be 3-4%). [111,112] However, the CL NR values of torasemide in the controls and the DMIS rats on the seventh day were comparable.…”

Tissue-specific alterations in expression and function of P-glycoprotein in streptozotocin-induced diabetic rats

“…Several reports have shown that diabetes may also alter the pharmacokinetic behavior of many drugs [1][2][3] , and these changes are generally associated with alterations in functional proteins, including cytochrome P450s (CYP450s) and efflux transporters, which participate in the absorption, metabolism, distribution and excretion of drugs.…”

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“…Oral anti-diabetic agents, such as chlorpropamide and glibenclamide, are anions at a physiological pH and have potent inhibitory effects on rOat1-mediated PAH uptake 10 , indicating that they are substrates of Oat1. Pharmacokinetic changes of drugs such as acetaminophen, furosemide, and methotrexate have been reported in rat model of diabetes mellitus induced by alloxan or streptozotocin treatment [11][12][13] .…”