Peak Urinary Excretion Research Articles

In-vivo sustained release of nanoencapsulated ferulic acid and its impact in induced diabetes

Diabetes mellitus (DM) is one of the most common lifestyle diseases, caused due to endocrine disorder. DM is commonly associated with hyperglycemia, a condition which is generally followed by an overproduction of free radicals leading to tissue oxidative stress. Currently, the focus of medical fraternity lies in developing therapeutic drugs based on natural origin in order to reduce the hyperglycemia associated toxicity. Ferulic acid (FA) is a ubiquitous hydroxycinnamic acid displaying an array of therapeutic properties, including anti-diabetic effect which could be attributed to its potent antioxidant capacity. However, due to low bioavailability and clinical efficacy of FA, its biomedical applications remained limited. In the present study, FA encapsulated chitosan nanoparticles (FANPs) were synthesized through ionotropic gelation process with an aim to enhance FA bioavailability. The plasma release and urinary excretion profiles of FANPs were compared with that of free FA using healthy Wistar albino rats as a model system. The encapsulated FA displayed extended plasma retention time and maximum plasma concentration was recorded at 60 min which implied four times enhancement of Tmax compared to free FA. The elimination of compound from the animal body also displayed a similar pattern where the peak urinary excretion of FA from nanoformulations. FANPs were also tested for their anti-hyperglycemic effects in streptozotocin (STZ) induced diabetes in Wistar albino rats and were found to attenuate the diabetes-associated symptoms. FANPs caused an enhancement in body weight, decrease in blood glucose level along with a regulatory effect on blood lipid profile of diabetic rats. Positive impact of FANPs in improving the hyperglycemic condition prevalent in diabetic rats might provide new avenues for the treatment of DM and help avoid secondary complications associated with the synthetic drugs.

Ethylmalonic and methylsuccinic aciduria in ethylmalonic encephalopathy arise from abnormal isoleucine metabolism

Ethylmalonic encephalopathy (EE), an organic aciduria of unknown etiology characterized by developmental delay, hypotonia, and vascular instability associated with lactic acidemia and urinary excretion of ethylmalonic acid (EMA) and methylsuccinic acid (MSA), has been described in 11 patients. To test the possibility that the underlying biochemical defect involves isoleucine catabolism, we determined the response to oral l-isoleucine (Ile) load (150 mg/kg) in a 5-year-old girl with EE and in three healthy, age- and sex-matched controls. Following Ile load in the patient, there was accumulation of 2-methylbutyrylglycine (2-MBG) and a delayed and lower peak urinary excretion of tiglylglycine (TGL), suggesting a partial defect in 2-methyl-branched chain acylcoenzyme A dehydrogenase (2M-BCAD). In vitro measurements 2M-BCAD activity in cultured skin fibroblasts from patients with EE have been reported to be normal. Our results show that isoleucine is a source for the elevated EMA and MSA in patients with EE, and suggest a functional, possibly secondary, deficiency of activity of 2M-BCAD in vivo.

Increased absorption of polysucrose, a marker of intestinal paracellular permeability, in Crohnʼs disease

Objective: To examine whether synthetic polysucrose behaves as a transcellular or paracellular marker in patients with Crohn's disease and in healthy subjects. Design: Patients with Crohn's disease (n=23) and age- and sex-matched healthy controls (n=22) were given an oral dose of polysucrose with a mean molecular weight of about 15 kDa, administered with a standard meal. Methods: Intestinal permeability to polysucrose was estimated as urinary excretion of the compound measured by immunoassay during 0–4, 4–8 and 8–12 h. Results: Urinary excretion values for polysucrose in the controls had a non-symmetrical frequency distribution and were not correlated to urinary volume. For the Crohn's disease group, intestinal permeability to polysucrose was significantly increased for the intervals 4–8 h and 8–12 h (P< 0.05). Permeability was more increased in small intestinal disease than in colonic disease, and more increased in active than in quiescent disease; hence, in patients with active Crohn's disease of the small intestine, intestinal permeability to polysucrose was significantly increased for all three time intervals (0–4, P< 0.05; 4–8 h, P< 0.001; 4–12 h, P< 0.01). Peak urinary excretion of polysucrose occurred later in the Crohn's disease patients than in the controls. Conclusions: Intestinal permeability to polysucrose is increased in Crohn's disease. In Crohn's disease patients and in healthy controls, polysucrose behaves as earlier described for known markers of paracellular intestinal permeability such as 51Cr-ethylenediamine tetraacetic acid (51Cr-EDTA) and lactulose. We conclude that polysucrose, which has the advantage of being both non-radioactive and resistant to bacterial degradation, may be used as such a marker.

Topical and systemic absorption of sodium pyrithione following topical application to the nails of the rhesus monkey.

A study was performed to investigate the local penetration into the nail, the systemic absorption into the rest of the body, and the routes of excretion of sodium pyrithione following topical application to the nail. Approximately 20 microliters of a film-forming 3% sodium 14C-pyrithione solution was applied once daily to 5 fingernails and 5 toenails of 4 rhesus monkeys for 6 or 7 days. Following dose removal on study day 7, 2 animals were sacrificed, and the treated nails were analyzed for radioactivity. The other 2 monkeys received the topical dose for 1 more day and were monitored during the postdosing period. Sodium 14C-pyrithione was absorbed slowly into and across the nail following topical application, with the nails serving as reservoirs for the drug. Further evidence of the slow movement of sodium pyrithione across the nail was provided by peak plasma 14C equivalents obtained on day 9, 1 day after the last dose had been removed from the nails. Only slight drug concentrations were measurable in plasma, with no radioactivity observed beyond day 12. The urinary excretion data exhibited a delay in peak urinary excretion (days 8 and 9), and an elimination half-life of 2 days, so that approximately 90% of the absorbed drug was eliminated within 1 week following treatment. Including a minor excretion pathway through the feces, total excretion as a percent of dosage was 8.5%, indicating that less than 10% of the applied topical dose of sodium pyrithione was absorbed systemically.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolism of cypermethrin in man: differences in urinary metabolite profiles following oral and dermal administration.

1. The pyrethroid insecticide cypermethrin was administered orally to six male volunteers as a single dose of 3.3 mg (cis: trans 1:1) and dermally to six volunteers at a dose of 31 mg/800 cm2 (cis:trans 56:44) as a soya oil-based formulation. Urine samples were collected for up to 5 days and analysed for the metabolites cis and trans 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCVA), 3-phenoxybenzoic acid (3PBA) and 3-(4'-hydroxyphenoxy) benzoic acid (4OH3PBA) following an acid hydrolysis procedure. 2. Following oral dosing approx. equal amounts of (cis+trans DCVA) and (3PBA+4OH3PBA) were excreted with peak excretion rates occurring between 8 and 24 h after dosing. The ratio of trans:cis DCVA was on average 2:1. Based on DCVA measurements the amount of cypermethrin absorbed was estimated to be between 27% and 57% (mean 36%) of the administered dose. 3. Peak urinary excretion rates of metabolites occurred between 12 and 36 h after dermal dosing. The amount of metabolites derived from the phenoxybenzyl moiety (3PBA+4OH3PBA) was on average 4 times greater than the amount of (cis+trans DCVA) recovered in urine. The ratio of trans:cis DCVA was, on average 1:1.2. Based on the recovery of the phenoxybenzyl metabolites it is estimated that 0.85-1.8% (mean 1.2%) of the administered cypermethrin was absorbed. 4. These studies demonstrate marked differences in the urinary metabolite profile by the two routes, and provide an improved basis for determining the extent and main route of absorption of cypermethrin under occupational exposure conditions.

Fluoride Metabolites After Prolonged Exposure of Volunteers and Patients to Desflurane

We examined the metabolism of desflurane in 13 healthy volunteers given 7.35 +/- 0.81 MAC-hours (mean +/- SD) of desflurane and 26 surgical patients given 3.08 +/- 1.84 MAC-hours (mean +/- SD). Markers of desflurane metabolism included fluoride ion measured via an ion-specific electrode, nonvolatile organic fluoride measured after sodium fusion of urine samples, and trifluoroacetic acid determined by a gas chromatographic-mass spectrometric method. In both volunteer and patient groups, postanesthesia serum fluoride ion concentrations did not differ from background fluoride ion concentrations. Similarly, postanesthesia urinary excretion of fluoride ion and organic fluoride in volunteers was comparable to preanesthesia excretion rates. However, small but significant levels of trifluoroacetic acid were found in both serum and urine from volunteers after exposure to desflurane. A peak serum concentration of 0.38 +/- 0.17 mumol/L of trifluoroacetic acid and a peak urinary excretion rate of 0.169 +/- 0.107 mumol/h were detected in volunteers at 24 h after desflurane exposure. Although these increases in trifluoroacetic acid after exposure to desflurane were statistically significant, they are approximately 10-fold less than levels seen after exposure to isoflurane. Thus, desflurane strongly resists biodegradation, but a small amount is metabolized in humans.

Bumetanide and furosemide in heart failure

We assessed the handling of and response to oral bumetanide (1.0 and 2.0 mg) and to furosemide (40 and 80 mg) in 20 patients with stable, compensated congestive heart failure (CHF), comparing the two drugs and, in addition, examining differences from normal subjects. Bumetanide and furosemide were similar in time course of absorption, but patients with CHF had considerably prolonged absorption compared to normal subjects causing attainment of lower peak concentrations of drug. In both CHF and normal subjects, more bumetanide than furosemide was absorbed. The elimination half-life of furosemide was approximately twice that of bumetanide, and both were about two times longer than respective values in normal subjects. "Dose"-response curves were shifted downward from normal with both drugs. In patients with CHF, overall response did not differ between bumetanide and furosemide. The two drugs exhibit subtle differences, the clinical importance of which appears to be negligible from this study. Importantly, however, both drugs showed delayed absorption causing attainment of peak urinary excretion rates of diuretic two- to threefold lower than in normal subjects. This effect along with the abnormal responsivity of the tubule may contribute to the "resistance" to oral doses of diuretics observed clinically even though no quantitative malabsorption of drug occurs.

Metabolic control in non-septic patients with musculoskeletal injuries

Changes in gaseous exchange, plasma substrates and hormones and excretion of nitrogen were followed in 13 non-septic male patients, all of whom had sustained at least 1 fracture of a long bone. Results were compared with normal subjects given glucose to produce a range of substrate and hormone concentrations. Over the 3 weeks following injury, oxidation of fat decreased from high levels whilst oxidation of carbohydrate rose. This reflected to some extent changes in availability of substrate, but early after injury oxidation of fat was higher than expected for the concentration of free fatty acids in plasma and later oxidation of carbohydrate was increased relative to concentrations of glucose and insulin. Concentrations of insulin in plasma were high for the prevailing concentrations of glucose, and peak urinary excretion of nitrogen coincided with maximum levels of insulin. It was concluded that in the injured patient there are changes at the level of utilization and oxidation of plasma substrates as well as in their availability, and that there is marked unresponsiveness of protein metabolism to the normal anabolic effect of insulin.

Antacid Effects on the Gastrointestinal Absorption of Riboflavin

□ The effect of aluminum hydroxide, magnesium hydroxide, and a combination of aluminum–magnesium hydroxide suspensions on the oral absorption of riboflavin was examined in five subjects. Coadministration of aluminum hydroxide or magnesium hydroxide suspension with riboflavin (30 mg) resulted in an increase in time of peak urinary excretion rate riboflavin when compared with control studies. There was no increase in the peak excretion rate or total urinary excretion of riboflavin when the antacid-treated subjects were compared to the control studies. In vitro experiments indicated that significant binding of riboflavin to the aluminum hydroxide and magnesium hydroxide suspensions occurred. The results of the present investigation are consistent with the reported effect of aluminum ion on GI motility and the known influence of gastric emptying on the absorption of riboflavin from the GI tract.

On the calculation of absorption rate constant of linear one-compartment open models using peak blood level or peak urinary excretion rate and post-absorptive data

On the calculation of absorption rate constant of linear one-compartment open models using peak blood level or peak urinary excretion rate and post-absorptive data

Some methods for estimating absorption rate constant of linear one-compartment open models

In previous reports methods of estimating absorption rate constant of linear one-compartment open models from peak blood level or peak urinary excretion rate and post-absorptive data have been given (Pidgeon and Pitlick, 1977, 1980; BarzegarJalali, 1982a). However, since it is unlikely that the peak values can be observed exactly experimentally. the absorption rate constant obtained from these methods might therefore not be accurate. In this communication, the parallel line method (Batzegar-Jalali, 1982b) will bc applied to the linear one-compartment open models (without or with lag time in absorption) to derive equations from which the absorption rate constant can be estimated from a single data point (for the model without lag time) or two data points (for the model with lag time) at the absorptive phase and postabsorptive data using blood or urine data. Some of the equations can also be employed for graphical determination of the rate constant. Details of the derivation of the equations are as follows. (1) The model without /ug time in absorption. The blood level curve for the model is described by Eqn. 1 (Gibaldi and Perrier, 1975)

Calculating absorption rate constant of linear one-compartment open models using peak blood level or peak urinary excretion rate and postabsorptive data

Calculating absorption rate constant of linear one-compartment open models using peak blood level or peak urinary excretion rate and postabsorptive data

Steroid levels after intramuscular injection of radioactive estradiol-17β, estrone, progesterone and testosterone in the bovine

Eight 2 year old Hereford cows from days 8 to 12 of the estrous cycle were injected intramuscularly with 5 ml of corn oil containing 5 mg of estradiol-17β (two cows), estrone (two cows), progesterone (two cows) or testosterone (two cows). Each cow treated with estradiol received 494 μc of estradiol-17β-6, 7 H 3 and each cow treated with estrone received 492 μc of estrone-6, 7 H 3. Each cow treated with progesterone or testosterone received 400 μc of H 3 compound labeled in the 7 position. Total urine was collected by urethral catheterization of the cows treated with estrogens. Blood samples for plasma and serum were collected via jugular cannulae. Blood and urine samples from estrogen-treated cows were collected hourly for the first 24 hr, at 2 hr intervals for the next 26 hr, at 4 hr intervals for the next 12 hr and at 12 hr intervals until background was reached. Blood samples were collected hourly from 1 to 8 hr after injection from progesterone or testosterone-treated cows. Plasma and serum levels of radioactive estradiol-17β, estrone, progesterone and testosterone were similar. Blood levels of radioactivity peaked at 2 hr post-injection in cows receiving estradiol-17β and at 3 hr in cows receiving estrone. Blood levels of labeled estradiol-17β and estrone were nondetectable by 54 hr and 83 hr, respectively. Peak urinary excretion of radioactivity was reached at 7 hr for estradiol-17β and at 14 hr for estrone and nondetectable levels were reached by 95 hr for estradiol-17β and 14 hr for estrone. At these times, 15.5% of the total dose of radioactive estradiol-17β and 17.5% of the injected estrone had been excreted in the urine. Peak blood and urinary excretion levels were reached earlier for radioactive estradiol-17β than for estrone, and excretion of estradiol-17β was completed more rapidly. No difference was found in plasma and serum levels for any steroid studies; thus, endogenous steroid titers in blood plasma and serum are not different in the cow.

Synthesis of 14C-Meglumine Salicylate and Its Disposition in Humans after Oral Administration

The synthesis of 14C-meglumine salicylate was accomplished by heating 14C-meglumine with salicylic acid, in equimolar ratios, in 2-propanol. The average radiochemical yield was 97.5%. Ten healthy adult male volunteers were given 1.2g of the compound orally. Five took 1.2g of 1-deoxy-l-[14C]-methylamino-D-glucitol salicylate (containing about 47μCi), and five others took 1.2g of 1-deoxy-l-methylamino-D-[U-14C]-glucitol salicylate (containing about 45μCi). Urine and feces were collected for 5 days, and blood was sampled for 24hr. The peak urinary excretion of meglumine and/or its metabolites occurred between 4 and 8hr after administration (about 7.2% of the administered dose). Meglumine was excreted primarily in the feces (72.4% over 5 days) and, to a smaller extent, in urine (21.3% over 5days). No activity was detected in blood. The excretion rate and percentage excreted were the same for both groups of subjects, suggesting that meglumine was not metabolized by N-demethylation or conversion to carbon dioxide. The highest blood salicylate level, 44.4±1.9μg/ml, was observed 1hr after administration. Urinary levels of salicylic acid and its metabolites were observed to be at a maximum at 8hr. Total salicylate recovery was 94.7±1.5% in 48hr. Salicyluric acid was the major metabolite, accounting for 69.5±3.6% of the dose. Salicylic acid accounted for 6.8±1.2%.

Pharmacokinetics of bethanidine in hypertensive patients.

The pharmacolinetics of bethanidine-14C was studied in three hypertensive patients. A 25-MG DOSE OF BETHANIDINE-14 C hemisulfate was administered intravenously. Plasma levels of drug were measured over the first 6 hr. In 3 to 4 days, 89% to 94% of the dose was excreted in the urine. Thin-layer chromatography (TLC) and isotope dilution analysis of the urine samples indicated that only intact bethanidine was excreted. Plasma level and urinary excretion rate profiles had miltiphasic characteristics. Estimated half-lives of the terminal phase ranged from 7 to 11 hr. Average renal clearance over the initial 6 hr approached renal plasma flow. In 2 of the patients, renal clearance between 2 and 4 hr after administration was reduced to one-helf that observed during the initial 2-hr period. After single oral administration of a 25-mg dose of bethanidine-14C hemisulfate, 48% of 61% was excreted in urine and 15% to 48% in feces. Peak urinary excretion rates were reached 6 hr following administration. The urinary excretion kinetics of bethanidine during and after repetive oral dosing was also studied. A 25-mg dose was dividied into 12 to 16 equal doses and administered avery 6 hr. A larger fraction of the cumulative dose was recovered in the urine (72% to 74%) than after the single dose, suggesting higher availability at the lower dose. Steady-state urinary excretion rates were achieved in 4 to 7 doses. The steady-state urinary excretion levels were consistent with pharmacolinetic predictions based on single oral dose data. When 2 of the patients were given imipramine for 2 days prior to an oral 25-mg dose of bethanidine-14C hemisulfate, the terminal half-lives of the urinary excretion rate profiles were shorter than those in the same patients not given imipramine.