Radioactivity In Urine Research Articles

Studies on the Pharmacokinetics of Ebselen in Rats (2): Absorption, Distribution and Excretion after Repeated Oral Administration.

The absorption, distribution and excretion of ebselen were investigated after repeated oral administration of 14C-ebselen to male rats at a daily dose of 50 mg/kg for a maximum of 21 days. 1. The blood levels of radioactivity at 24 hr after dosing reached a steady state by 17th do sing, indicating 4 times higher level than that at the first dosing. After 21st dosing, the blood level of radioactivity reached the Cmax of 8.04 μg equiv. to ebselen/ml at 2 hr after dosing, eliminated with a half life (t1/2) of 2.37 hr (2-4 hr), reached the second peak at 8 hr and then eliminated with t1/2 of 8.64 day (24-168 hr). The Cmax after 21st dosing was 1.6 times higher, and the elimination rate from 24 hr after dosing was slower, than those parameters in single dosing. 2. After 21st dosing, the level of radioactivity in the limb joint was 7 times higher than that in single dosing, the levels in the liver, testis and lung were 3-4 times higher, and those in the other tissues were 2 times or less. After final dosing, the levels of radioactivity in thyroid gland and blood cells at 576 hr after dosing were still 41% and 24% of their respective maximum levels, showing relatively slower elimination rates than those observed in the other tissues. 3. The cumulative excreti on of radioactivity in urine and feces did not change with the number of dosing after 4th dosing, ranging from 50.2 to 54.7% and from 45.4 to 48.3%, respectively, up to 24 hr after every daily dosing.

Studies on the Pharmacokinetics of Ebselen in Rats (3): Absorption, Distribution and Excretion after Administration of 75Se-labelled Compound.

In order to clarify whether ebselen, 2-phenyl-1, 2-benzisoselenazol-3(2H)-one is metabolized to liberate its selenium atom as an inorganic compound(s) or not in vivo, blood level of radioactivity and excretion of radioactivity in urine and feces were determined, and whole body autoradiograms were prepared after oral administration of 75Se-ebselen (50 mg/kg) or intravenous injection of Na275SeO3, an inorganic selenium compound, as a control (1 mg/kg) to male rats. Following results were obtained: 1. For 75Se-ebselen dosing group, the mean blood levels of radioactivity reached the Cmax of 29.17 nmol eq. to ebselen/ml (8.00 μg eq./ml) at 1 hr and declined with a half-life, t1/2 of 7.6 hr from 2 to 24 hr after dosing. For Na275SeO3 dosing group, the blood level of radioactivity was 57.75 nmol eq. to Na275SeO3/ml (9.99 μgeq./ml) at the first sampling time and thereafter declined slowly with a half-life, t1/2 of 190 hr from 24 to 168 hr after dosing. 2. For 75Se-ebselen dosing group, the highest levels of radioactivity were observed in the gastric and intestinal contents, followed by fat, brown fat and liver, showing higher radioactivity than that in blood. The overall distribution of radioactivity decreased with time and the radioactivity was not detected at 168 hr after dosing. For Na275SeO3 dosing group, high levels of radioactivity remained in liver, kidney and blood even at 168 hr after dosing. 3. For 75Se-ebselen dosing group, within 168 hr after dosing, 53.8% of the dosed radioactivity was excreted in urine, and 45.8% of that in feces. The residual radioactivity in the carcass was not detected. For Na275SeO3 dosing group, within 168 hr after dosing, 44.8% of the dosed radioactivity was excreted in urine, and 8.0% of that in feces. The radioactivity remained in the carcass, being 41.1% of the dose. From the results above, the extent of inorganic selenium release from ebselen was estimated to be 0.0% of the dose.

Pharmacokinetic Studies of Betotastine Besilate (TAU-284). (II): Distribution and Excretion after Repeated Oral Administration, and Transfer into the Fetus and Milk of Rats.

The distribution and excretion of radioactivity was studied following a 21-day period of daily oral administration of 14C-TAU-284 to male rats. Furthermore, the transfer of radioactivity into the fetus and milk was also studied on the 12th and 18th day of pregnancy in rats, and in lactating female rats. 1. When measured at 24 hrs after each of 21 repeated dosings to male rats with 14-C-TAU-284, the levels of radioactivity in the blood reached the steady-state by the 16th dosing. The decrease of radioactivity in blood after repeated dosings for 21 days was slower than that after a single dosing. 2. In the distribution of radioactivity after the 21st dosing, the radioactivity in the liver and kidney was higher than that in other tissues. The radioactivity in cerebrum, eye balls, fat, seminal vesicles and testis were low. And radioactivity levels in other tissues were moderate. The tissue levels of radioactivity increased after each dosing during repeated administration. 3. Transfer to blood cells also increased by repeated dosing. Most radioactivity in blood cell was associated with a globin fraction. 4. The total ex cretion of radioactivity in urine and feces during each 24 hrs after daily dosing was almost constant. 5. The levels of radioactivity in the fetal liver 30 minutes after oral administration to 18th day in pregnant rats were about the same as in maternal plasma. The levels of radioactivity in other fetal tissues were 1/3 to 1/10 of that in maternal plasma. 6. The radioactivity level in the milk reached a maximum (0.40 μg eq./ml) at 1 hr after oral administration to 11 day-lactating rats. The radioactivity in milk 48 hrs after dosing was bellow the detection limit. The radioactivity in milk at each measured time was higher than that in plasma of lactating rat.

Studies on the Metabolic Fate of Lamivudine (III): Absorption, Metabolism and Excretion of Lamivudine in Dogs.

The absorption, metabolism and excretion of nucleoside analogue, lamivudine, were investigated after a single oral administration of 3H-lamivudine to male and female dogs at a dose of 2 mg/kg. 1. The total radioactivity in plasma reached the maximum at 0.9 hour after oral administration to male dogs and declined rapidly with a half-life of 2.9 hours. The concentrations of lamivudine in plasma reached the maximum at 0.8 hour after oral administration and declined with a half-life of 1.4 hours. Profiles of the plasma levels of total radioactivity or lamivudine in female dogs were similar to those in male dogs. 2. The ratio of plasma protein binding of radioactivity was below 17% and the ratio of distribution to erythrocytes of radioactivity was 35-38%, after oral administration to male dogs. 3. The excreted radioactivity in urine and feces was 85.3% and 9.5% of the dose in male dogs, respectively, 93.2% and 5.8% in female dogs within 168 hours after oral administration. 4. Lamivudine and two major metabolites, trans-sulphoxide of lamivudine and cytosine, were observed by the radio-HPLC analysis of urine collected from male and female dogs after oral administration.

Clinical Pharmacokinetics of Lercanidipine

Summary:(±) Lercanidipine hydrochloride (HCl) (Zanidip) is an antihypertensive drug structurally related to dihydropyridine calcium-entry blockers: lercanidipine is weakly basic (pK′a = 6.83 at 37°C) and highly lipophilic (log P octan-1-ol/water = 6 at 20-25°C). After oral administration of 10-20-mg

Modulation of organ uptake of 11C-labelled L-DOPA

The present study was undertaken to investigate if pretreatment with pharmacological agents could change the organ uptake of 11C-labelled l-DOPA, and especially if the urinary excretion could be decreased. l-[β- 11C]DOPA was injected IV into unanesthetized Sprague-Dawley rats. After 20 min the rats were decapitated and organs taken out for radioactivity measurements. The uptake in the organs was investigated in animals only given the tracer, and in animals pretreated with drugs such as decarboxylase inhibitors carbidopa and benserazide as well as the monoamine oxidase inhibitors deprenyl, clorgyline, and the COMT inhibitor OR-486. A marked decrease in the urinary radioactivity was observed after carbidopa and benserazide administration. HPLC analysis revealed that under native conditions the major part of urinary radioactivity existed as dopamine, which was eliminated by the decarboxylase inhibitors. After pretreatment with the COMT inhibitor OR-486, the radioactivity uptake in the pancreas increased fourfold as compared to non-treated animals. HPLC analysis showed that this correlated with a marked increase in radiolabelled DOPAC. In the other organs and with the other drugs, only small effects were observed. With l-[β- 11C]fluoroDOPA as a tracer, similar results were observed although the increase in the pancreas by OR-486 had a lower magnitude. These studies suggest that it might be possible to improve the diagnostic ratio of l-[β- 11C]DOPA or l-[ 18F]fluoroDOPA in whole-body PET studies by pretreating the patient with decarboxylase inhibitor for reducing the urinary excretion and potentially increase the target organ uptake by COMT inhibition.

The elimination of secretory leukocyte protease inhibitor (SLPI) from the gastrointestinal tract in man

Nyström M, Bergenfeldt M, Ohlsson K. The elimination of secretory leukocyte protease inhibitor from the gastrointestinal tract in man. Scand J Clin Lab Invest 1997; 57:119-126Secretory leukocyte protease inhibitor (SLPI) is the dominant protease inhibitor in the mucus secretions of the genital and respiratory tract and it was recently also detected in intestinal mucosa. Furthermore an earlier study showed high concentrations of SLPI in peritoneal fluid from patients with perforations of the large and small intestines. As SLPI is acid-stable, this raised the question of to what extent swallowed SLPI may contribute. The present study investigated the turnover of swallowed SLPI in the gastrointestinal tract. Native 125I-labelled SLPI was instilled in the duodenum of three healthy volunteers and radioactivity in plasma, faeces and urine was measured. Within 72 h 81.4% of the injected radioactivity was excreted in urine and 3.6% in faeces as radioactive low molecular weight proteins (> 1 kDa). Recombinant human SLPI (rh-SLPI) was incubated with porcine pepsin or human gastric or duodenal juice. This resulted in rapid degradation of SLPI to smaller molecules. In conclusion, SLPI is rapidly degraded in the stomach and duodenum. There were no measurable amounts of SLPI in the faeces. We have shown that during normal conditions, swallowed SLPI was rapidly degraded in the stomach and duodenum, and therefore it probably can not be of any importance for inflammatory diseases in the intestines.

Distribution, elimination, and residues of [14C]clenbuterol HCl in Holstein calves.

Clenbuterol HCl is a beta-adrenergic agonist that has been used illegally in Europe and the United States by some livestock producers to increase carcass leanness. The objectives of this study were to determine the metabolic disposition, distribution of radioactivity, and the concentrations of parent clenbuterol in tissues after a single oral dose of [14C] clenbuterol HCl in calves. [14C]Clenbuterol HCl (1.59 microCi/mg, 3 mg/kg BW) was administered to a 74- and a 96-kg Holstein bull calf as a single oral dose. Blood samples were taken at 1, 3, 6, 12, 24, 36, and 48 h after dosing; urine and feces were collected separately and placed into respective pools from 0 to 6, 6 to 12, 12 to 24, 24 to 36, and 36 to 48 h after dosing. At 48 h after dosing, calves were anesthetized and exsanguinated, and visceral organs, bile, eyes, brain, skeletal muscle, skin, adipose tissue, and the remainder of the carcass were collected. Tissues were processed by coarse grinding through a Hobart grinder, followed by homogenization on dry ice. Eyes were dissected and the various tissues and excreta were assayed for total radiocarbon content by combustion analysis and(or) liquid scintillation counting. Parent clenbuterol was measured in selected tissues by HPLC after solvent extraction. Urinary, fecal, and carcass radioactivity averaged 41.5 +/- 8.1, 2.4 +/- .4, and 52.3 +/- 8.7% of the dose, respectively (mean +/- SD.). Average total recovery of radiocarbon was 96.2 +/- .4%. Radioactive residues present in carcasses averaged (ppm; mean +/- SD.): blood, .6 +/- .2; heart, 1.4 +/- .0; lungs, 8.4 +/- 1.7; spleen, 2.6 +/- .3; liver, 5.0 +/- .4; kidney, 5.9 +/- .0; brain, 1.9 +/- .4; adipose tissue, 1.1 +/- .2; rumen, reticulum, omasum, abomasum, 2.3 +/- .4; small intestine, 3.2 +/- .3; large intestine, 4.0 +/- .4; skeletal muscle, 1.0 +/- .2; bile, 12.5 +/- 4.0; white skin, .7 +/- .1; black skin, 4.0 +/- .7; remainder of the carcass, 1.0 +/- .2. Ocular residues were as follows: aqueous humor, 6.3 +/- 1.2; cornea, 13.5 +/- 8.6; iris, 255.8 +/- 167.0; lens, 2.3 +/- 1.5; vitreous humor, 2.2 +/- .4; retina/choroid, 84.5 +/- 34.1; sclera, 11.1 +/- 2.1. Mean concentrations of parent clenbuterol in tissues were (ppm; mean +/- SD): lung, 6.8 +/- .9; liver, 2.2 +/- .5; kidney, 3.7 +/- .5; and heart, .9 +/- .1. Parent clenbuterol represented from 43.9% of the total residue in liver to 81.2% of the total residue in lung.

Disposition of Taltirelin. (2): The Transfers into the Fetus and Milk, Sex-Related Difference after Single Oral Administration and Blood Concentration after Repeated Oral Dosing in Rats.

The transfers of 14C-taltirelin into the fetus and milk and sex-related difference were investigated after a single oral administration of 14C-taltirelin at a dose of 3 mg/kg to rats. The blood level after repeat ed oral dosing was also studied. 1. In pregnant rats on the 13th and 19th day of pregnancy, the levels of radioactivity in whole fetus reached the maximum levels at 3 hr after oral administration, which accounted for 1/7 and 1/3 of the maternal blood concentration, respectively. At 3 hr, the transfered radioactivity in fetus of 19th day pregnant rats was less than 0.002% of dose per one fetus. 2. In lactating rats on the 14th day af ter delivery, levels of radioactivity in the blood and milk at 1 hr after dosing were 11.0 and 8.9 ng eq./g, respectively. The radioactivity in the milk decreased more slowly than that in blood and the radioactivity level in the milk was about 2 times higher than the corresponding blood level from 6hr after dosing. 3. There were no significant sex-related differences in the pharmacokinetic parameters of blood radioactivity and urinary excretion. MDOA, found in the urine of male and female rats, accounted for approximately 18 and 30% of urinary radioactivity, respectively, but any sex difference in kind of urinary metabolite was not observed. 4. After 15 times repeated oral administrations to male rats, the Cmax, t1/2 and AUCinf values of blood radioactivity increased by 1.3, 2.2 and 3.1 times compared with those after the first dosing, respectively. The blood level of radioactivity at 1 hr after each dosing reached steady-state within 7 times dosing.

Metabolic Fate of the Environmental Mutagen 3-Nitrofluoranthene in the Rat

Abstract 3-Nitrofluoranthene, a potent environmental mutagen, was administered to rats intraperitoneally at 10 mg/kg, labelled with 14C. Urine contained 15 to 20% of the dose, eliminated mainly within the first 24 hours after dosing. Over 95% of the radioactivity in unhydrolysed urine chromatographed with the solvent front in a reverse-phase HPLC system, indicating extensive conjugation. After hydrolysis with β-glucuronidase (containing sulfatase) and concentration on C18-Sep-Pak, urine was fractionated by HPLC for further characterization. NMR analysis of the metabolite fractions indicated that positions 4, 8 and 9 were major sites of oxidation. Both acetamide and amine derivatives were formed. The finding of multiple oxidation and incomplete acetylation is in contrast to the fate of 1-nitropyrene, where 1-acetamidopyren-6-ol, itself a potent mutagen, represents the major metabolic product. This difference in metabolism pathways may have implications for the genotoxicity of 3-nitrofluoranthene.

Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression

Transgenic CYP2E1 knockout mice (cyp2e1-/-) were used toinvestigate the involvement of CYP2E1 in the in vivo metabolism of benzene and in the development of benzene-induced toxicity. After benzene exposure, absence of CYP2E1 protein was confirmed by Western blot analysis of mouse liver samples. For the metabolism studies, male cyp2e1-/- and wild-type control mice were exposed to 200 ppm benzene, along with a radiolabeled tracer dose of [14C]benzene (1.0 Ci/mol) by nose-only inhalation for 6 hr. Total urinary radioactivity and all radiolabeled individual metabolites were reduced in urine of cyp2e1-/- mice compared to wild-type controls during the 48-hr period after benzene exposure. In addition, a significantly greater percentage of total urinary radioactivity could be accounted for as phenylsulfate conjugates in cyp2e1-/- mice compared to wild-type mice, indicating the importance of CYP2E1 in oxidation of phenol following benzene exposure in normal mice. For the toxicity studies, male cyp2e1-/- wild-type, and B6C3F1 mice were exposed by whole-body inhalation to 0 ppm (control) or 200 ppm benzene, 6 hr/day for 5 days. On Day 5, blood, bone marrow, thymus, and spleen were removed for evaluation of micronuclei frequencies and tissue cellularities. No benzene-induced cytotoxicity or genotoxicity was observed in cyp2e1-/- mice. In contrast, benzene exposure resulted in severe genotoxicity and. cytotoxicity in both wild-type and B6C3F1 mice. These studies conclusively demonstrate that CYP2E1 is the major determinant of in vivo benzene metabolism and benzene-induced myelotoxicity in mice.

Metabolism of 5 alpha-dihydroprogesterone in women and men: 3 beta- and 3 alpha-,6 alpha-dihydroxy-5 alpha-pregnan-20-ones are major urinary metabolites.

The metabolism of 5 alpha-dihydroprogesterone (5 alpha-DHP) in women and men was evaluated by defining the pattern and identity of selected metabolites excreted in urine after the iv infusion of radiolabeled 5 alpha-DHP. Virtually all of the radioactivity in urine (approximately 37% of the administered dose) was excreted within 72 h. Quantitatively, the 2 major urinary metabolites of 5 alpha-DHP in each of 13 studies conducted in 7 women and 2 men were 3 beta,6 alpha-dihydroxy-5 alpha-pregnan-20-one and 5 alpha-pregnane-3 alpha,20 alpha-diol, which could be extracted after beta-glucuronidase, but not solvolysis, treatment of the urine. Radiolabeled 3 alpha,6 alpha dihydroxy-5 alpha-pregnan-20-one (glucuronoside), in lesser amounts, also was identified in the urine of each subject. The 3 alpha/beta, 6 alpha-dihydroxy-5 alpha-pregnan-20-ones arise through specific extrahepatic pathways of progesterone/5 alpha-DHP metabolism. These metabolites are not the products of the enzyme reaction catalyzed by the cytochrome P450 steroid 6 alpha-hydroxylase of human liver (and other tissues), which affects the 6 alpha-hydroxylation of C19- and C21-delta 4-3-ketosteroids (e.g., progesterone, testosterone, and cortisol), but does not act upon 5 alpha-reduced steroids. Moreover, the steroid 5 alpha-reductases do not act upon 6 alpha-hydroxy-delta 4-3-ketosteroids. In addition, the 6 alpha-hydroxylation of 5 alpha-reduced-3 alpha/beta-hydroxysteroids is not demonstrable in adult liver tissue. Rather, the formation of 6 alpha-hydroxylated-5 alpha-pregnane-3 alpha/beta-ol-20-ones is indicative of an extrahepatic pathway of progesterone metabolism, viz. progesterone-->5 alpha-DHP-->5 alpha-pregnan-3 beta/alpha-ol-20-one(s)-->3 beta/alpha,6 alpha-dihydroxy-5 alpha-pregnan-20-one(s), in which 5 alpha-pregnan-3 alpha/beta-ol-20-ones are metabolized by an enzyme(s) that catalyzes the 6 alpha-hydroxylation of saturated substrates. There are important differences among mammalian species in the enzymes that catalyze the C-6-hydroxylation of 5 alpha-reduced C19- and C(21)-3 beta/alpha-hydroxysteroids, but in all species studied, these enzymatic reactions are the final steps in the extrahepatic inactivation of 5 alpha-reduced bioactive metabolites of progesterone (or testosterone).

Pharmacokinetics and metabolism of N-(2-hydroxyethyl)-2,5-[14C]-pyrrolidine (HEP, Epolamine) in male healthy volunteers.

N-(2-hydroxyethyl)-pyrrolidine (HEP, Epolamine) is a strong base used to salify organic acids of pharmaceutical interest in order to improve their solubility in water. Diclofenac-HEP (Flector) is the first example of an epolamine salt of a drug. In this study, [14C]-HEP was administered by oral route (300 mg, about 50 microCi/subject) to 3 volunteers with the aim to investigate its plasma profile and to calculate the relevant pharmacokinetic parameters. The experimental data correlated with a two-compartment pharmacokinetic model. Total radioactivity in urine and faeces was also measured. The radioactivity was excreted preferentially by the faecal route (about 65% of the dose administered in the 0-72 h collection interval). Urinary excretion accounted for about 30% of the dose and occurred very rapidly (about 22% of the dose was in the 0-8 h collection interval). Metabolic investigations were carried out on urine samples. TLC analysis with radioscan detector indicated a main radioactive zone, accounting for about 98% of the radioactivity in the plate. After scraping off and purification of the radioactive areas, the compound isolated (Met I) was analysed by gas chromatography-mass spectrometry with electron-impact ionization process. The structure of the metabolite was postulated to be pyrrolidine N-oxide.

Excretory Fate of Estradiol and Progesterone in the African Elephant (Loxodonta africana) and Patterns of Fecal Steroid Concentrations throughout the Estrous Cycle

We developed and validated a noninvasive method to quantify fecal estrogens and progestins as a tool for monitoring long-term ovarian activity in free-ranging African elephants. The lag times between iv injection of [3H]estradiol and [14C]progesterone and peak excretion of radioactivity in urine and feces were approximately 4 hr and 48 hr, respectively. The majority of progesterone metabolites recovered was excreted in feces (55%) versus urine (45%), whereas comparatively little of the recovered estradiol metabolites were excreted in feces (5%) compared to urine (95%). Intrasample variation in fecal hormone concentrations was extremely high but could be substantially reduced by extracting well-mixed fecal powder from freeze-dried samples, taken from the central or premixed portion of the wet sample. This method resulted in a close correspondence between matched serum and fecal progestins (mean correlation = 0.81, range 0.61–0.94) collected from five nonpregnant adult females over a 7-month period. Fecal estrogen profiles were more ambiguous, tending to overlap with those of fecal progestins. We conclude that analyses of fecal progestins can provide an effective, noninvasive means of characterizing ovarian activity in free-ranging African elephants.

Excretion of infused 14C-steroid hormones via faeces and urine in domestic livestock

Abstract The aim of this comparative study was to gain more information about the excretion of steroid hormones in farm animals. This should help to establish or improve non-invasive steroid monitoring procedures, especially in zoo and wildlife animals. Over a period of 4 h the 14C-steroid hormones (3.7 MBq) progesterone (three females), testosterone (three males), cortisol and oestrone (two males, two females) were infused intravenously in sheep, ponies and pigs. Faeces were collected immediately after defecation. Urine was sampled via a permanent catheter in females and after spontaneous urination in males. A total of 88 ± 10% (mean ± SD) of the administered radioactivity was recovered. Considerable interspecies differences were measured both in the amounts of steroid metabolites excreted via faeces or urine and the time course of excretion. Progesterone and oestrone in ewes, and progesterone in mares were excreted mainly in the faeces (over 75%). The primary route of excretion of all other 14C-steroids was via the urine but to a different extent. In general, sheep showed the highest degree of faecal excretion and pigs the least. The highest radioactivity in urine (per mmol creatinine) was observed during the infusion or in one of the next two samples thereafter, whereas in faeces it was measured about 12 h (sheep), 24 h (ponies) or 48 h (pigs) after the end of the infusion. Thereafter the radioactivity declined and reached background levels within 2–3 weeks. In faeces, steroid metabolites were present mainly in an unconjugated form, but in blood and urine as conjugates. Mean retention time of faecal radioactivity suggested that the passage rate of digesta (duodenum to rectum) played an important role in the time course of the excretion of steroids. The information derived from this investigation could improve the precision of sampling as well as the extraction of steroids from the faeces. Furthermore, the study demonstrates that it should be possible to establish methods for measuring faecal androgen and cortisol metabolites for assessing male reproductive endocrinology and stress in animals.

125Iodine-iothalamate clearance in children. A simple method to measure glomerular filtration

Glomerular filtration rate (GFR) is the most widely used test to evaluate renal function. Several clearance markers have been used to measure GFR in adults. In children, however, a simple and reliable method to measure GFR is not available. Renal 125iodine (I)-iothalamate clearance, after a single subcutaneous injection, is a simple and accurate test to measure GFR in adults. The validity of unlabelled iothalamate, as a marker for measurement of GFR in children, was reported recently. Unfortunately, the unlabelled iothalamate assay is arduous. We report our experience with a single subcutaneous injection of 125I-iothalamate to measure GFR in normal children and those with renal disease. A weight-adjusted dosing regimen was adopted. This regimen resulted in sufficient above-background radioactivity in both blood and urine for reproducible measurement of GFR. Intra-test variability for GFR was not affected by the degree of renal insufficiency. The test was well tolerated with only 2 patients developing mild headache during the procedure. Our study showed that renal clearance of 125I-iothalamate is reproducible, simple, and practical in healthy children and those with mild and advanced renal disease.

Cortisol metabolism in the domestic cat and implications for non-invasive monitoring of adrenocortical function in endangered felids

Three domestic cats were given i.m. injections of 3H-cortisol to determine the time course and relative proportion of excreted 3H-cortisol metabolites into urine and feces. Most urinary radioactivity was detected in the first sample collected at 3.9 ± 2.5 hr postinjection and accounted for 13.9 ± 2.1% of the total radioactivity recovered. High performance liquid chromatography (HPLC) detected four urinary metabolites, one of which (13.7% urinary radioactivity) eluted with the 3H-cortisol reference tracer and was quantifiable using a commercial cortisol radioimmunoassay (RIA). The majority of cortisol metabolites in feces (85.9 ± 2.1%) was excreted at 22.3 ± 6.2 hr. HPLC analysis detected several fecal metabolites consisting primarily of nonhydolyzable water-soluble forms, none of which eluted with 3H-cortisol or 3H-corticosterone reference tracers. No immunoreactivity was detected in HPLC-separated fecal eluates using the cortisol RIA; however, two of the more polar metabolites were quantifiable using a commerical cortisosterone RIA. The physiological relevance of the immunoreactive fecal metabolites was determined in four domestic cats given an adrenocorticotropin (ACTH) challenge. Increased serum cortisol concentrations were detected within 30 min of ACTH injection, which was maintained for at least 6 hr. A corresponding increase in fecal cortisol metabolite concentrations (ranging from 238% to 826% over individual baseline values) was observed 24–48 hr later. These data indicate that adrenocortical activity can be monitored nonivasively in the cat by measuring cortisol metabolites excreted in feces. This procedure is a potentially valuable tool for endangered felid management to help evaluate responses to physiological and psychological stressors associated with environmental conditions and husbandry practices. (This article is a US Government work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.

Cortisol metabolism in the domestic cat and implications for non‐invasive monitoring of adrenocortical function in endangered felids

Three domestic cats were given i.m. injections of 3H-cortisol to determine the time course and relative proportion of excreted 3H-cortisol metabolites into urine and feces. Most urinary radioactivity was detected in the first sample collected at 3.9 ± 2.5 hr postinjection and accounted for 13.9 ± 2.1% of the total radioactivity recovered. High performance liquid chromatography (HPLC) detected four urinary metabolites, one of which (13.7% urinary radioactivity) eluted with the 3H-cortisol reference tracer and was quantifiable using a commercial cortisol radioimmunoassay (RIA). The majority of cortisol metabolites in feces (85.9 ± 2.1%) was excreted at 22.3 ± 6.2 hr. HPLC analysis detected several fecal metabolites consisting primarily of nonhydolyzable water-soluble forms, none of which eluted with 3H-cortisol or 3H-corticosterone reference tracers. No immunoreactivity was detected in HPLC-separated fecal eluates using the cortisol RIA; however, two of the more polar metabolites were quantifiable using a commerical cortisosterone RIA. The physiological relevance of the immunoreactive fecal metabolites was determined in four domestic cats given an adrenocorticotropin (ACTH) challenge. Increased serum cortisol concentrations were detected within 30 min of ACTH injection, which was maintained for at least 6 hr. A corresponding increase in fecal cortisol metabolite concentrations (ranging from 238% to 826% over individual baseline values) was observed 24–48 hr later. These data indicate that adrenocortical activity can be monitored nonivasively in the cat by measuring cortisol metabolites excreted in feces. This procedure is a potentially valuable tool for endangered felid management to help evaluate responses to physiological and psychological stressors associated with environmental conditions and husbandry practices. (This article is a US Government work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.

Metabolism of 2,3,5,6-tetrachloronitrobenzene (tecnazene) in rat.

1. The metabolic fate of [U-14C]-2,3,5,6-tetrachloronitrobenzene (tecnazene) has been determined in the male and female rat following a single dose of 1 mg/kg and in surgically prepared, bile-duct-cannulated rats following a single oral dose of 135 mg/kg. 2. Radioactivity in the female rat was excreted mainly in urine (82%). The male rat, however, excreted approximately equal amounts of radioactivity in urine and faeces (the latter via bile). 3. The principal metabolic pathway was conjugation with glutathione (GSH) and concomitant nitro-displacement. The GSH-conjugate and related metabolites were excreted in the bile and ultimately in the urine as the mercapturic acid conjugate. The cysteine conjugate underwent beta-lyase-mediated metabolism to yield a thiol that underwent subsequent methylation to the thioanisole followed by S-oxidation. 4. A novel tetrachloromethyldisulphide metabolite was also formed.

Metabolic Fate of YM866, a Novel Fibrinolytic Agent (I). Plasma Concentration, Distribution, Metabolism and Excretion in Rats after Single Intravenous Administration.

We investigated the plasma concentration profile, distribution, metabolism and excretion of radioactivity after a single intravenous administration of 125I-YM866 in male rats. 1. After a single intravenous administration of 125I-YM866, more than 50% of this drug rapidly formed two high molecular complexes with plasma proteins. The ratio of trichloroacetic acid (TCA)-precipitable radioactivity to total radioactivity in plasma decreased with time, suggesting that this drug is metabolized into low molecular weight metabolite or free 125I. Immunoreactive YM866 concentrations decreased more rapidly than total or TCA-precipitable radioactivity. 2. After a single intravenous adminis tration of 125I-YM866, radioactivity levels were highest in the plasma, followed by whole blood, liver, kidney, adrenal gland, spleen, lung, pituitary gland and thyroid. Radioactivity levels in these tissues were one-quarter or half of that in the plasma, and the level in the brain was much lower than in the plasma. Except for the uptake of the released 125I by some specific tissues, the radioactivity in most tissues decreased rapidly. Although most of the radioactivity in tissues were precipitable with TCA at an early stage after administration, the ratio of TCA-precipitate to total radioacivity decreased rapidly with time. 3. After a single intr avenous administration of 125I-YM866, 91.2% and 3.9% of the dosed radioactivity was excreted in urine and feces within 144 hr, respectively. Most of the radioactivity in urine was not precipitable with TCA and eluted in the gel filtration chromatographic (GFC) analysis at a low molecular region, suggesting that the radioactivity was excreted as low molecular weight materials 4. The concentration of 125I-YM866 in plasma was higher than that of 125I-tissue plasminogen activator (125I-t-PA), probably because 125I-YM866 was distributed less extensively to the liver than 125I-t-PA.