Mean Daily Excretion Research Articles

Presence of carbazole and polyhalogenated carbazoles in human urine

Exposure to carbazole (CZ) and polyhalogenated carbazoles (PHCZs) may pose a threat to human health, owing to their potential dioxin-like toxicity. Until now, the presence of these chemicals in the human urine from the general population is still unclear. Human urine samples (n = 210) were taken from the general population in Quzhou, China in this study, and were analyzed for CZ and 14 PHCZs. CZ and nine PHCZs were detected in collected human urine. CZ (detection frequency 100 %), 3-chlorocarbazole (3-CCZ; 88 %), 3,6-dichlorocarbzole (36-CCZ; 84 %), and 3-bromocarbazole (3-BCZ; 80 %) were more frequently detected. Among detected PHCZs, 3-CCZ (mean 0.49 ng/mL, < LOD–4.3 ng/mL) had comparatively higher urinary levels, followed by 3-BCZ (0.30 ng/L, < LOD–1.9 ng/mL) and 36-CCZ (0.20 ng/L, < LOD–1.4 ng/mL). Urinary concentrations of CZ in male participants (1.3 ± 0.26 ng/mL) were significantly (p < 0.05) higher than that in female participants (0.92 ± 0.24 ng/mL). No obvious trend in urinary concentrations with the age of participants was found for CZ and detected PHCZs. The mean daily excretion was found highest for CZ (31 ng/kg bw/day), followed by 3-CCZ (19 ng/kg bw/day) and 3-BCZ (8.5 ng/kg bw/day). This study provides the first data, to our knowledge, on the presence and levels of CZ and PHCZs in human urine, which is necessary for conducting the human exposure risk assessment.

Assessment of Pharmacodynamic Equivalence and Tolerability of Lanthanum Carbonate Oral Powder and Tablet Formulations: A Single-Center, Randomized, Open-Label, 2-Period Crossover Study in Healthy Subjects

BackgroundPhosphate binders are commonly used in tablet form to help patients with hyperphosphatemia limit their absorption of dietary phosphate. These patients frequently have a heavy tablet burden so alternative formulations provide choice and may support adherence. Lanthanum carbonate (LC) is a phosphate binder currently available as a chewable tablet. This study was conducted to support an application for marketing authorization for the oral powder formulation within the European Union. ObjectiveThe goal of this study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of an oral powder formulation of LC compared with the reference chewable tablet formulation. MethodsA Phase I, single-center, randomized, open-label, 2-period, crossover study to assess pharmacodynamic equivalence of the 2 formulations was conducted in healthy adults aged 18 to 55 years receiving a diet standardized for phosphate content. Individuals were randomized to receive a different formulation in each period, taking 10 doses of 1000-mg LC at 3000 mg/d per period with an intervening washout of ≥14 days. The primary pharmacodynamic variable was mean daily excretion of urinary phosphorus over 3 days while receiving LC. Pharmacodynamic equivalence was confirmed if the 90% CI for the difference between formulations in least squares (LS) mean excreted urinary phosphorus was within ±20% of the LS mean value for the tablet formulation. Secondary end points included determination of pharmacokinetic parameters and assessment of tolerability by recording of adverse events. ResultsIn total, 72 individuals entered the study. They were predominantly men (72.2%), with a mean (SD) age of 31.4 (8.26) years and a BMI of 25.8 (2.45) kg/m2. The LS mean (SE) excreted urinary phosphorus was 16.8 (0.48) mmol/d during administration of LC tablets (±20% = ±3.35 mmol/d). The corresponding value during administration of LC oral powder was 15.2 (0.48) mmol/d; 90% CI for the difference between formulations was −2.38 to −0.82 mmol/d, confirming pharmacodynamic equivalence. The most common adverse events were gastrointestinal, and no serious adverse events were recorded. ConclusionsIn this multiple-dose study, the oral powder and tablet formulations of LC were well tolerated and met the regulatory criteria for pharmacodynamic equivalence in these healthy volunteers. ClinicalTrials.gov identifier: NCT00880750.

Abnormal diurnal changes in in-vivo platelet activation in patients with atherosclerotic diseases

We measured the urinary excretion of beta-thromboglobulin in timed urine samples collected by 2 groups of healthy volunteers, (group I, n = 20, mean age 34 years, group II, n = 15, mean age 64 years) and by patients (n = 40) with symptomatic atherosclerotic diseases. Older healthy subjects were found to excrete high amounts of BTG in comparison to young subjects (302.25 ± 50.61 vs 219.65 ± 59.31 ng/day, P < 0.05). Higher ( P < 0.01) levels of urinary BTG were observed in patients with coronary (427.61 ± 179.96 ng/day), cerebral (422.13 ± 223.2 ng/day) and peripheral (454.16 ± 269.05 ng/day) arterial diseases and in diabetic patients with diffuse vascular complications (613.71 ± 253.07 ng/day). The diurnal variability of BTG excretion, measured as coefficient of variation (C.V. %) of the mean daily excretion rate, was higher ( P < 0.001) in atherosclerotic patients (70.59 ± 26.57) as compared with the similar values observed in the control groups of young (32.05 ± 14.54) and older subjects (26.38 ± 8.4). Comparable diurnal variabilities of the creatinine excretion rate were observed in the control groups and in patients. These data indicated that in vivo platelet activation may occur in atherosclerotic patients with a distinctive high fluctuation rate.

Circadian rhythmicity of the urinary excretion of mercury, potassium and catecholamines in unconventional shift-work systems.

The round the clock urinary excretion rates of mercury were assessed for two series of unconventional patterns of activity and sleep in subjects who were not exposed to occupational, medical, or other obvious sources of mercury. In the first series the urine was collected in 3-h periods from six subjects during the first and last 2 d of a four-week, continuous 6-h shift (car ferry, watches either 0800--1400 and 2000--0200 or 1400--2000 and 0200--0800). In the second series the urine was collected in 4-h periods from five subjects working an 8-h experimental rotation shift compressed into 5 d (work two mornings--8-h interval--work two nights--8-h interval--work two afternoons). The mean daily excretion rate of the 11 subjects (48 investigation days, 334 urine samples) was 14.5 pmol of mercury/min (range 5.5--24.4 pmol of mercury/min). The mercury excretion oscillated regularly during 24 h by +/- 20--25% of the individual's daily mean excretion rates. The peak excretion rates were found at 0652 in the first and 0642 in the second series (cosinor treatment). Due to the circadian rhythm the mean 24-h excretion rates were best represented (correlation coefficient 0.92) by analyses of urine produced around noon (spot samples, collection periods 1100--1400 and 1000-1400, respectively). The circadian oscillations of mercury excretion were not influenced by the widely different and varying activity-sleep patterns of the two series. The rhythmicity of potassium excretion (peaks at around 1400) was more irregular. The stable oscillations of mercury excretion contrasted most with the excretion of adrenaline and noradrenaline, which, without losing the basic 24-h rhythmicity, closely followed the unconventional patterns of activity and sleep.

Effect of anticonvulsant drugs on the rate of folate catabolism in mice.

An increase in folate catabolism has been suggested as the cause of the folate deficiency observed in many clinical conditions, including chronic anticonvulsant therapy. Previous studies have shown that the radioactive catabolites, excreted after an equilibration period of 3 d, consisted exclusively of folates that had been cleaved to produce pteridines and p-aminobenzoylglutamate, most of which was excreted as acetamidobenzoylglutamate. We have developed an experimental animal model using mice to determine the rate of catabolism of [3H]pteroylglutamate (folic acid) by the quantitative estimation of [3H]p-aminobenzoylglutamate and [3H]acetamidobenzoylglutamate in urine. Administration of diphenylhydantoin at three different doses (0.5, 20, and 50 mg/kg) significantly increased the rate of catabolism as measured by an increase in both the mean daily excretion and the cumulative excretion of these catabolites. Administration of intramuscular phenobarbitone on the other hand, did not affect the rate of catabolism, when compared with controls.

Muscle-Protein Catabolism after Injury in Man, as Measured by Urinary Excretion of 3-Methylhistidine

1. Urinary excretion of 3-methylhistidine, an index of the rate of muscle breakdown, has been measured during the first 7 days in patients after elective surgery or accidental injury. 2. There was no major difference between the mean daily excretion after skin grafting or total hip replacement, or in injured patients who were hyperketonaemic for the first 24 h after admission. 3. The group of injured patients who did not develop hyperketonaemia had a mean urinary 3-methylhistidine excretion which was twice that of the other groups. 4. It is concluded that increased breakdown of muscle protein makes a major contribution to the greater urinary nitrogen excretion in the normoketonaemic group of injured patients.

Sodium excretion during pregnancy and pseudopregnancy in the rabbit.

In a recent study of renal function in supposedly pregnant rabbits, much time and effort was wasted because about half the mated females failed to become pregnant. On retrospective analysis, the daily sodium excretion was different in the animals which became pregnant as compared with those which failed to become pregnant and which were presumably pseudopregnant. The main difference was apparent on day 4 after mating. We are now using sodium excretion as a simple diagnostic test of pregnancy in rabbits. Fifteen animals were kept in metabolism cages for 20 days before mating and for the duration of the supposed pregnancy. Only eight of the 15 actually became pregnant. All the urine excreted by each animal each day was collected, its volume measured and its sodium concentration estimated by flame photometry. For each animal the mean daily excretion during the 20-day control period was defined as 100%. Figure 1 shows

The estimation of 3,4-dihydroxymandelic acid in urine and its excretion by man.

Abstract A method is described for the estimation of 3,4-dihydroxymandelic acid (DHMA) in human urine. It consists of the following steps: adsorption of DHMA on a column of alumina, passage of the alumina eluate through a column of cation exchange resin, extraction of DHMA into ethyl acetate, conversion of DHMA to protocatechuic aldehyde by shaking the ethyl acetate extract with aqueous ammonia, extraction of the aldehyde into ethyl acetate, evaporation of the extract, and solution of the residue in absolute methanol. Protocatechuic aldehyde is estimated by the increase of fluorescence affected by the addition of a trace of concentrated sulfuric acid. An internal standard is analyzed with every sample. The specificity of the method is high; in particular, it is free from interference from 3,4-dihydroxyphenylacetic acid. No evidence was found for the presence of an acid-hydrolyzable conjugate of DHMA in urine. The mean daily excretion rate was found to be of the order of 100 μg. Excretion rates in cases of pheochromocytoma may be about ten times as high as the normal average.

Nonhormonal iodine escape from the normal and abnormal thyroid gland.

ABSTRACT A kinetic analysis of iodine metabolism was performed on 7 normal subjects on an iodine-restricted diet, 7 normal subjects and 7 subjects with simple goiter on the usual Japanese diet. 1) The mean intrathyroidal iodine content was 12.2, 27.6 and 43.3 mg/gland, respectively. 2) The escape of nonhormonal iodine from the thyroid gland was confirmed in all cases despite the restriction of dietary iodine. 3) After the occurrence of leveling off of the daily urinary excretion of 131I, the mean daily excretion rate of urinary 131I (E*) was 5 times greater than the mean daily degradation rate of labeled hormonal iodine in the extrathyroidal organic iodine pool (D*) and was 3 times greater than the mean daily secretion rate of the labeled hormonal iodine from the gland (H*). 4) The ratio of the mean daily excretion rate of urinary 131I (E*) to the mean daily secretion rate of PB131I from the gland (H*) was used as one of the indices for the release of nonhormonal iodine. The relationship in 19 subjects be...

Urinary cortisol and 6β-hydroxycortisol in the monkey, Cebus albifrons: Normal variation and the effects of ACTH and phenobarbital

The urinary excretion of unconjugated cortisol and 6β-hydroxycortisol has been studied in the New World monkey Cebus albifrons. The mean values of cortisol in male 3-year-old (2–3 kg) untreated monkeys as determined by the Porter-Silber reaction after chromatographic purifications (using tracer tritiated cortisol to correct for procedural loss) was 170 μg/24 hours. The respective mean daily excretion of 6β-hydroxycortisol (using the mean cortisol recovery to correct for procedural loss) was 100 μg/24 hours. There was a considerable day-to-day variability in the urinary excretion of both steroids exhibiting a mean coefficient of variation of 60%. ACTH administration caused a seven- and a five-fold increase in the excretion of cortisol and 6β-hydroxycortisol, respectively, over control levels. Stress of restraint in a chair elicited a five- and three-fold increase, respectively. The average cortisol: 6β-hydroxycortisol ratios obtained for the control, ACTH and stress periods were 1:0.6, 1:0.4, and 1:0.3. Phenobarbital in two consecutive experiments caused a significant increase in the urinary excretion of 6β-hydroxycortisol and led to an inversion of the ratio of cortisol: 6β-hydroxycortisol in favor of the latter. Cortisol and 6β-hydroxycortisol were eluted and identified from the chromatograms used in the determinations. The response to phenobarbital in Cebus albifrons was comparable to that observed in man and indicates the value of this species for further investigations concerning 6β-hydroxylation of cortisol.

Influence of E. coli infection on turnover and metabolism of cholic acid in germ-free rats

The fecal excretion of cholic acid and its metabolites has been determined in normal and germ-free rats and in rats monoinfected with Escherichia coli. The mean daily excretion was 5.1, 1.9, and 2.2 mg. in the respective groups. The mean values for the amount of cholic acid and its metabolites in the intestinal tract were 14.6, 18.4, and 20.8 mg., respectively. 7-Ketodeoxycholic acid and 3α,7β,12α-trihydroxycholanic acid are formed from cholic acid in E. coli monoinfected rats. 7-Ketodeoxycholic acid is formed by microbial enzymes and is then slowly reduced by liver enzymes to cholic acid and 3α,7β,12α-trihydroxycholanic acid.