Relationship between urinary excretion rate, steady-state plasma levels and diuretic response of furosemide in the rat

The purpose of the present study was to determine if furosemide's active transport process could be saturated at therapeutic concentrations and to define a relationship between furosemide in a measurable sampling compartment and its diuretic effect. The experiments utilized Sprague-Dawley rats, ranging in weight from 248 to 313 g, anesthetized with sodium pentobarbital (60 mg/kg). The femoral artery and vein as well as the bladder were cannulated, and samples were taken to measure inulin and furosemide concentrations. 28 rats were infused, after a suitable loading dose (0.5--1.5 mg/kg), to steady-state plasma furosemide levels over the therapeutic concentration range 0.8--25.1 micrograms/ml. Total renal clearance (corrected for kidney function as measured by inulin clearance) showed a negative correlation with plasma concentration (r = -0.655 p less than 0.001), and a good correlation was found between urine flow rate and the urinary excretion rate of furosemide (r = 0.777, p less than 0.001). Steady-state plasma levels of furosemide showed a poor correlation with urine flow rate (r = 0.377, p greater than 0.10).     

Urinary excretion of methaqualone-N-oxide in man.

1. Oral administration of therapeutic doses (250 mg) of methaqualone (Melsed) to adult human subjects gives rise to the urinary excretion of methaqualone-N-oxide. This metabolite has been identified by chromatography and mass spectrometry and quantitatively determined by reduction with titanium trichloride to methaqualone which was then determined by g.l.c. 2. The N-oxide accounts for 5-9% of the dose in 24 h. 3. 2-Nitrobenzo-o-toluidide, a possible oxidation product of methaqualone-N-oxide, has not been detected. 4. The urinary excretion of unchanged methaqualone is less than 0-3% of the dose. The ease with which methaqualone-N-oxide is thermally converted to methaqualone casts doubts on the previously published figures for the urinary excretion of methaqualone.     

Urinary excretion of p-hydroxylated methamphetamine metabolites in man

p-Hydroxymethamphetamine and p-hydroxyamphetamine in urine samples from methamphetamine addicts were analyzed by high-performance liquid chromatography-electrochemistry (HPLC-EC). The urine samples were hydrolyzed with equal volumes of 12 N HCl at 60 °C for 4 h and were then diluted with water and neutralized with NaOH solution. The neutralized urine was passed through a solid phase extraction column, Bond-Elut^® C₁₈, and after washing, the substances were eluted with acidified acetonitrile. The eluate was evaporated under a stream of nitrogen. The residue was dissolved in 0.1 N PCA and a small volume of the aliquots was injected into the HPLC. This procedure for determination quantitated both free and conjugated forms of the metabolites together. Thereby we could determine concentrations of the metabolites in minute urine samples; i.e., from 2.5 l urine. The free form of the metabolites alone was analyzed by the same procedure except for hydrolysis of the conjugates.Concentrations of methamphetamine, p-hydroxymethamphetamine and p-hydroxyamphetamine in the urine samples of addicts collected at arbitrary times were determined by this procedure or by gas chromatography. It was found that there was no correlation between the concentration of methamphetamine and that of the metabolites. This investigation also revealed that various ratios between the concentrations generally were scattered over a wide range of percentages.     

Urinary catecholamine excretion following lysergic acid diethylamide in man

Summary Two separate controlled experiments in man measured the excretion of epinephrine, norepinephrine, vanilmandelic acid (VMA) and total metanephrines following lysergic acid diethylamide (LSD), comparisons being made with an injection of a similar dose of epinephrine in the one instance and with a no-treament period in the other. LSD (2 mcg/kg) produced insignificant changes in urinary catecholamine excretion over a four-hour period while epinephrine (3 mcg/kg) evoked substantial increases in excretion of epinephrine, VMA and metanephrines with a concomitant decrease in norepinephrine excretion. Sympathomimetic effects of these doses of LSD were apparent clinically and as judged by the degree of elevation of plasma free fatty acids (FFA); the response to epinephrine was brief and intense, while that to LSD was sustained and more gradual in onset. In the second experiment, LSD (1.5 and 2 mcg/kg) produced no more changes in catecholamine excretion over an eight-hour period than a control no-treatment trial.Although LSD has many sympathomimetic actions, these are not adequately reflected by measurement of urinary catecholamine excretion. These experiments suggest that measurement of urinary catecholamines is a poor gauge of sustained sympathomimetic effects.This work was supported in part by grant MH-03030, National Institutes of Health.     

Urinary excretion of c-hydroxy derivatives of methaqualone in man.

1. Six monohydroxy metabolites of methaqualone have been identified by g.l.c.-mass spectrometry in the urine of healthy human subjects who received therapeutic doses (250 mg) of the drug (Melsed) daily for ten day. 2. The three major metabolites were 2-methyl-3-(2'-hydroxymethylphenyl)-4(3H)-quinazolinone, 2-methyl-3-(2'-methyl-3'-hydroxyphenyl)-4(3H)-quinazolinone and 2-methyl-3-(2'-methyl-4'-hydroxyphenyl)-4(3H)-quinazolinone. Three minor metabolites in descending order of importance were 2-hydroxymethyl-3-o-tolyl-4(3H)-quinazolinone, 2-methyl-6-hydroxy-3-o-tolyl-4(3H)-quinazolinone and 2-methyl-8-hydroxy-3-o-tolyl-4(3H)-quinazolinone. 3. The 8-hydroxy metabolite is identified as a urinary metabolite or methaqualone in humans for the first time.     

Multiple linear regression modeling of furosemide renal clearance and urinary excretion rate.

Multiple linear regression techniques were utilized to determine models for the renal clearance and urinary excretion rate of furosemide. Models for the renal clearance were formulated based on data collected from the literature. The best model predicted that the weight-normalized renal clearance was a function of the weight-normalized creatinine clearance, with coefficient values dependent on the presence or absence of heart, liver, and/or kidney failure. The predictive performance of this model was evaluated using a separate verification data set, and, prospectively, for a group of cardiac patients. The urinary excretion rate of furosemide is the primary determinate of response. Models for the furosemide excretion rate were formulated from data collected prospectively from a group of patients with cardiac disease. The best model predicted that the dose-normalized morning urinary excretion rate was a function of the blood urea nitrogen concentration (BUN), with modifications for the presence of liver failure and/or decompensated heart failure. The oral dosage required to produce a clinically optimal furosemide excretion rate in cardiac patients without liver disease was dose (mg) = 42.1/(0.925-0.0151 BUN).     

Bucolome, a potent binding inhibitor for furosemide, alters the pharmacokinetics and diuretic effect of furosemide: potential for use of bucolome to restore diuretic response in nephrotic syndrome.

To determine whether bucolome (5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhydropyrimidine), a nonsteroidal anti-inflammatory agent, can reverse diuretic resistance of furosemide in patients with nephrotic syndrome, we examined the inhibitory effect of bucolome on the protein binding of furosemide in serum and urine. Bucolome significantly inhibited the protein binding of furosemide not only in serum but also in urine of preparation albumin (UPA), which mimics urinary albumin concentration in patients with nephrotic syndrome by ultrafiltration method. The binding percentage of furosemide to albumin was approximately 70% in UPA. With coadministration of bucolome to healthy volunteers, renal clearance of furosemide was increased, reflecting the increase of the free fraction of furosemide in serum. Furthermore, coadministration of bucolome caused a significant increase of urine volume and sodium concentration in urine. Even at higher urine levels of furosemide, the inhibitory effect of bucolome on the protein binding of furosemide in UPA remains constant, and changes in pH at weakly acidic pH levels (pH 5.5-6.5) did not alter the inhibitory effect of bucolome. Interestingly, coadministration of bucolome with furosemide in doxorubicin (Adriamycin)-induced nephrotic syndrome model rats alleviated the diuretic resistance. These results suggest that bucolome has a potent inhibitory effect on the protein binding of furosemide in the urine and can partially restore the diuretic response of furosemide in patients with nephrotic syndrome by increasing the free fraction of furosemide at the site of action.     

Urinary excretion of selegiline N-oxide,a new indicator for selegiline administration in man

1. The metabolism of selegiline (SG) has been studied by investigating the time-course of urinary excretion of SG and its metabolites using high-performance liquid chromatography-electrospray ionization mass spectrometry (LC-ESI MS) in combination with solid-phase extraction. 2. The excretion profiles of SG and its four major metabolites, selegiline-N-oxide (SGO), N-desmethylselegiline (DM-SG), methamphetamine (MA) and amphetamine (AP), were investigated in six healthy volunteers after oral administrations of SG hydrochloride in a single dose of 2.5 or 7.5mg, and a repeat twice-daily dose of 5.0 mg day(-1) (for 3 days). 3. The cumulative amount of SGO excreted within approximately the first 8-12h was comparable with MA, and the amount in the first 72 h was 2.0-7.8 times larger (2.8-13.2% of the dose) than that of DM-SG. 4. These results demonstrate that SGO can be used in place of DM-SG, which is known to be a main specific metabolite of SG, as a new indicator for the discrimination of SG use compared with MA abuse.     

Urinary excretion of an uracilic metabolite from caffeine by rat,monkey and man

Caffeine (C) metabolism has been studied in rat, monkey (Macaca cynomolgus) and man after oral administration of the compound. Eleven metabolites were quantified in urine; particular attention has been drawn to 4-amino [5-formyl methylamino]1,3-dimethyl uracil (ADMU) because of its structural analogies with 5-fluorouracil. The rat has been found to produce a much larger fraction of ADMU (about 30%) in respect to monkey and man (1–2%). The potential toxicological implications of this findings are discussed.     

Studies on urinary excretion of the potassium-retaining diuretic amiloride (Desmethyl-pipazuroyl-guanidine,MK 870) in man

Summary 1. A spectrophotofluorometric procedure is described by which the potassium-retaining diuretic amiloride is isolated from the urine by means of thin-layer chromatography. - 2. After administering single doses of 10 mg, the drug can be demonstrated in the urine up to 24 h, and after giving 20 mg, up to 48 h. The percentage recovered is independent of the dosage applied and is not influenced by diuresis, or by the concomitant administration of the saluretic, etacrynic acid. In patients with cirrhosis of the liver and portal hypertension the recovery of amiloride is identical to that of healthy controls. After fasting for four hours following the ingestion of the drug, the quantity of the diuretic excreted in the urine is approximately twice that after administration of amiloride at breakfast or shortly before.