Research Techniques in the Rat

Petty, Clayton; Fink, B. Raymond

doi:10.1097/00000542-198301000-00027

Cited by 18 publications

(16 citation statements)

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“…In addition to biliary elimination, mezlocillin is actively secreted by the renal tubules. The low-dose CL' (5.49 ± 2.02 ml/min) exceeds the average glomerular filtration rate of the rat as measured by inulin clearance (-3 ml/min) (14), suggesting net active tubular secretion. The high-dose CL' (2.34 ± 0.83 ml/min) approximates the glomerular filtration rate, indicating saturation of tubular secretion.…”

Section: Discussionmentioning

confidence: 82%

Dose-dependent pharmacokinetics of mezlocillin in rats

Jungbluth

Jusko

1989

Antimicrob Agents Chemother

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The pharmacokinetics of mezlocillin were examined in rats following bolus intravenous doses of 20 or 200 mg/kg. Mezlocillin exhibited bi-or triexponential disposition profiles, and the area under the concentrationtime curve increased nonproportionally with dose similar to reported findings in humans. Apparent total, renal, and nonrenal clearances and the volume of distribution at steady-state all decreased by 45 to 50% with the higher dose, and the elimination half-life was longer (8 2 versus 15 3 min). Mezlociliin exhibits low saturable binding in rat serum, ranging from 20 to 40% bound. Pharmacokinetic parameters based on free drug demonstrated dose-dependent characteristics similar to those with total drug. Use of the volume of distribution from the low dose allowed calculation of the true mean residence time. The linear relationship between dose and mean residence time from free concentrations yielded pooled Michaelis-Menten parameters. These were used as initial estimates in the simultaneous nonlinear fitting of the low-and high-dose mean free concentrations to a three-compartment model with sequential distribution and Michaelis-Menten elimination to describe the nonlinearity of mezlocillin disposition further.The pharmacokinetics of mezlocillin are dose dependent in healthy volunteers (1) and in subjects with renal dysfunction (12). This phenomenon has generally been attributed to decreased total, renal, and nonrenal clearances with larger doses (1, 12). Concentration-dependent plasma protein binding and smaller central and total volumes of distribution have also been reported with larger doses of mezlocillin (1,12,17).A significant portion of the nonrenal clearance of mezlocillin has been attributed to biliary excretion of unchanged drug (2, 6, 7). Both renal and nonrenal clearances are decreased when the drug is coadministered with probenecid, suggesting that dual active secretion processes exist (19). Saturation of biliary as well as renal excretion mechanisms may occur with mezlocillin (1, 6, 12). However, one study indicated that these excretion pathways were not saturable and that another process may account for mezlocillin nonlinearity (7).This study evaluates the mechanism(s) responsible for the nonlinear disposition of mezlocillin by examining the protein binding and renal and nonrenal excretion in rats following two dose levels of mezlocillin. The utility of moment analysis for providing initial estimates for nonlinear curve fitting is also examined. MATERIALS AND METHODSStudy design. A cannula was implanted into the jugular veins of eight male Sprague-Dawley rats (350 to 500 g) under light ether anesthesia, and the rats were then placed in a restraining cage. Normal saline was infused at 1 ml/h to keep the cannula patent. Rats were dosed 1 h after waking with 20 or 200 mg of mezlocillin sodium (Miles Pharmaceuticals) per kg. Four rats were used for each group. Blood samples (0.3 ml) were drawn serially at appropriate times (as illustrated in Fig. 2 and 4), and the serum was separated and frozen ...

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Section: Discussionmentioning

confidence: 82%

Dose-dependent pharmacokinetics of mezlocillin in rats

Jungbluth

Jusko

1989

Antimicrob Agents Chemother

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“…18 Plasma potassium levels were slightly above normal values, probably the result of a mild degree of hemolysis during sampling or processing of the blood. 18 The plasma samples of rats of groups 5 and 6 were unavailable for analysis. There were no statistically significant differences between the plasma electrolytes in the various groups.…”

Section: Studymentioning

confidence: 95%

Prostanoids and aldosterone-induced mild experimental hypertension in rats.

et al. 1990

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The goal of this study was to determine the role of prostanoids in a new model of mineralocorticoid-dependent hypertension induced by the subcutaneous infusion of aldosterone (1 fig/hT) to normal male Sprague-Dawley rats. This regimen caused a mild and gradual increase in systolic pressure over a period of 4 weeks (113±1 vs. 137±3 mm Hg) and was associated with an increase in the in vivo formation of prostaglandins I 2 and Ej and of thromboxane A 2 in the kidney. High sodium intake induced a fall in the urinary levels of prostaglandin E? aQ d a rise in the arterial pressure of control rats (126±1 vs. 113±1 mm Hg) but did not influence aldosterone-induced hypertension. Indomethacin (3.0 nig/kg/day) caused a profound inhibition of the in vivo synthesis of prostaglandin I 2 and thromboxane A 2 without modifying the renal production of prostaglandin E 2 . Although indomethacin exerted no effect on aldosterone-induced hypertension in rats fed a normal diet, it caused a further rise in systolic pressure in aldosterone-treated rats fed a high sodium diet (157±6 vs. 140±4 mm Hg). The results of this study in a model of aldosterone-induced mild hypertension in the rat indicate that 1) aldosterone exerts a stimulatory effect on the renal synthesis of prostanoids, particularly prostaglandin E?; 2) thromboxane A 2 and prostaglandin I 2 do not seem to play a role in aldosterone-induced hypertension under conditions of normal dietary salt intake, whereas the role of prostaglandin E 2 is unclear; 3) there is enough sodium in a normal diet to allow for the maximal expression of the hypertensive effect of aldosterone; 4) prostaglandin I 2 seems to play a significant role in modulating the cardiovascular impact of a high sodium diet in aldosteronetreated rats; and 5) the renal biosynthesis of prostaglandin E 2 is particularly resistant to the inhibitory effect of indomethacin in vivo. induced a further fall in blood pressure, suggesting that the concomitant formation of a pressor prostanoid could contribute to mineralocorticoid-induced severe hypertension. However, these models, which combine mineralocorticoid administration with uninephrectomy or the addition of sodium chloride to drinking water at an isosmolar or hyperosmolar concentration, are situations rarely encountered in clinical medicine.The objective of the present study was to investigate the role of prostanoids in a model of mineralocorticoidinduced hypertension that resembles more closely human primary aldosteronism. The results include the influence of aldosterone, dietary salt, and indomethacin on the systolic arterial pressure and the in vivo biosynthesis of PGI 2 and PGE2 and of TXA 2 , in a model of hypertension induced by the chronic subcutaneous administration of aldosterone in normal Sprague-Dawley rats.

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“…The surgical cut down to the external jugular vein and catheter implantation can be accomplished using a variety of methods and materials. A common method for laboratory rats has been previously described (1), and citations for numerous other methods have been compiled (2). These methods of cannulation often require complete isolation of the jugular vein and as a result may produce considerable surgical trauma, post-operative discomfort and a prolonged recovery.…”

Section: Following Limited Isolation Of the Vein By Blunt Dissectionmentioning

confidence: 99%