Metabolism and disposition of 1,4,7,8-tetrachlorodibenzo-p-dioxin in rats

Metabolism studies of 1,4,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a relatively nontoxic dioxin congener, were undertaken to gain a better understanding of mammalian metabolism of dioxins without the problems associated with the use of the most toxic congener, 2,3,7,8-TCDD. 14C-1,4,7,8-TCDD was dosed to conventional and bile-cannulated rats at a level of 8 mg/kg. The 14C was excreted almost entirely in 72 hours with the major routes of excretion feces and bile. Metabolites were identified from the feces, bile, and urine by GC-MS or negative ion FAB MS and 1H NMR. The two major fecal metabolites were hydroxylated tetra- and triCDDs. Glucuronide and sulfate conjugates of these hydroxyl metabolites were found in the urine and bile. Minor metabolites included dichlorocatechol, dihydroxylated tetra- and triCDDs, and conjugates of these compounds.     

Excretion and metabolism of tipredane, a novel glucocorticoid, in the rat, mouse, monkey, and human

The excretion and metabolism of [3H]tipredane, a novel glucocorticoid, has been studied in mice, rats, marmosets, rhesus and cynomolgus monkeys, and humans. After oral administration, [3H]tipredane was rapidly absorbed, metabolized, and excreted into urine and feces. In mice and male rats, radioactivity was excreted primarily into feces or bile, whereas in female rats, monkeys, and humans, excretion was mainly via the renal route. Some sex differences in the proportions excreted into urine and feces were noted in rodents, with females eliminating relatively more radioactivity in urine. Tipredane was shown to be extensively metabolized, but the routes were highly species-dependent and, in the rat, they were sex-dependent. Unchanged tipredane was not detected in any urine, bile, or blood extracts. Urinary and blood extract profiles indicated that there were between 10 and 30 metabolites in rats and mice, the majority of which constituted < 2% of the dose. In these species, the major pathways involved loss of the thioethyl moiety, S-oxidation of the thiomethyl group, and saturation of the adjacent saturated C16-17 bond. Hydroxylation of the steroid B-ring was seen in the 7 alpha-position in mice and female rats, and in the 6 beta-position in male rats. Metabolism of tipredane in rhesus and cynomolgus monkeys and humans was similar, but less extensive and different to that seen in rodents. The major products, the 6 beta-hydroxylated sulfoxide and sulfone metabolites of tipredane, accounted for 21-36% of the dose in human and monkey urine, and were also major components in blood. In contrast to mice and rats, S-oxidation and an unsaturated C16-17 bond were evident in primates. Metabolism of tipredane was rapid and complex, with significant species differences, although the disposition in rhesus and cynomolgus monkeys seemed to be similar to humans.     

Studies on the toxicology of hexachlorobenzene. II. Identification and determination of metabolites

Female rats were dosed intraperitoneally with 14C-hexaxhlorobenzene. The drug was administered on 2 or 3 occasions. The total doses amounted to 260 and 390 mg/kg 14C-hexachlorobenzene, respectively. Urine and feces from the animals were collected over a period of 4 weeks after the first injection. Both excreta and some tissues of the animals were examined for their content of radioactivity and for hexachlorobenzene and its metabolites. Gas chromatography, isotope dilution analysis, and combined gas chromatography-mass spectrometry were used to identify the metabolites of hexachlorobenzene. In urine pentachlorophenol, tetrachlorohydroquinone, and pentachlorothiophenol were present as major metabolites. One of the isomers of tetrachlorothiophenol was present as a minor metabolite. In the feces pentachlorophenol and pentachlorothiophenol only were identified. At the end of the experiment, carbon-14 excreted with urine and feces amounted to 7% and 27%, respectively, of the radioactivity administered. More than 90% of carbon-14 excreted in urine was contained in the major metabolites. In the feces about 30% of the excreted radioactivity was bound to metabolites and about 70% was contained in the unchanged drug, while in the tissues of the animals only pentachlorophenol was detected in measurable amounts, accounting for 10% of label in blood and less than 0.1% of carbon-14 determined in body fat. Total radioactivity contained in the metabolites detected in the animal body and in the excreta at the end of the experiment accounted for about 16% of the administered radioactivity.     

The molecular mechanism of temperature enhancement of proton magnetic relaxation rates in methaemoprotein solutions. III. The effect of sixth ligand in high-spin derivatives

Levels of cefazolin were determined in plasma, urine, bile, and cerebrospinal fluid in humans after a bolus intravenous injection and during a controlled, continuous intravenous infusion. All the patients were studied in a steady-state and crossover fashion. In plasma, the mean peak level after bolus injection (1.5 g) studied in 12 patients was 206.5 mug/ml; during continuous infusion (6 g daily), the mean level remained stable at 52.6 mug/ml. With bolus injection and continuous infusion, respectively, 89.7 and 86.3% of the administered dose of cefazolin were excreted in the urine of nine patients over the 6-h period considered. The levels of cefazolin in common bile duct bile were studied in six cholecystectomized patients. In bile collected during the two 3-h periods of the experiment, the mean concentration of the drug in the bile after bolus injection was 66.9 and 22.0 mug/ml, respectively; during continuous infusion, the corresponding biliary levels were 50.7 and 51.3 mug/ml, respectively. In four neurosurgical patients with an intraventricular catheter, neither bolus injection nor continuous infusion resulted in a demonstrable concentration of cefazolin in the cerebrospinal fluid. The continuous intravenous administration of cefazolin might have some advantage over the intravenous bolus intermittent injections. In plasma, the area under the curve is greater with continuous infusion than with bolus injection. In bile, the levels of cefazolin are more sustained with continuous infusion than with bolus injection. This approach to intravenous administration of cefazolin deserves more pharmacological and clinical trials.     

Analysis of (CAG)n size heterogeneity in somatic and sperm cell DNA from intermediate and expanded Huntington disease gene carriers

Various kinds of lipophilic peptides were prepared by acylation of an alpha-helical peptide, mastoparan, to investigate the effects of acyl groups on the interaction of peptides with phospholipid membranes. alpha-Helicity of the peptides was increased by introduction of long acyl groups. Acyl peptides showed different membrane-perturbation activities for neutral and acidic phospholipid vesicles, whereas a peptide with a dialkycarbamoyl group always exhibited a strong activity. High hemolytic activities were observed for the peptides with long acyls (single or double chain). These results indicate that lipophilic groups introduced to mastoparan contribute greatly to the interaction of the peptide with phospholipid membranes with lengthening of the acyl chain and that the structural character of the lipophilic group also influences the conformation of the peptide.     

Metabolism of 14C-labelled alphaxalone in man

The metabolism of 14C-labelled alphaxalone, dispensed as Althesin, was studied in normal patients, patients with obstructive jaundice and patients with chronic renal disease and anuria. The radioactive label was removed rapidly from the plasma following i.v. administration. The major portion of the label was excreted in the urine. In patients with normal renal function 14C-labelled alphaxalone is probably taken up by the liver, metabolized to a more polar compound and excreted in the urine; a small amount is excreted in the bile. In the patient with anuria, hepatic uptake appears to be relatively normal and the length of action of Althesin is not prolonged. It is assumed that in such patients the eventual route of excretion is via the bile and faeces.     

Tissue distribution, metabolism, and clearance of the convulsant trimethylolpropane phosphate in rats

The distribution, metabolism, and clearance of trimethylolpropane phosphate (TMPP), a potent, bicyclophosphate, gamma-aminobutyric acid-ergic convulsant, were studied in male Fischer-344 rats. Intraperitoneal administration of TMPP was compared with oral gavage with respect to rates of absorption, distribution, and clearance. Distribution of TMPP to major body tissues was evaluated for the first 24 hr after administration or, in the case of regional brain distribution, immediately after the first TMPP-induced clinical seizure. Samples purified from the urine, feces, and bile of rats exposed to TMPP, as well as from rat liver microsomes incubated with TMPP in vitro, were analyzed for possible phase I and phase II metabolism, using HPLC. The disposition and clearance of TMPP in the blood and major body tissues were measured. TMPP was found to be well distributed to highly vascularized tissue compartments, with little retention >24 hr after administration. TMPP was eliminated through the urine and feces as the parent compound, with no evidence of phase I or phase II metabolism. TMPP was rapidly cleared from the blood during the first 30 min after exposure, with slower clearance of >87% of the drug during the following 8-hr period and >99.5% clearance by 100 hr after injection. Repeated daily exposure to TMPP for up to 5 successive days resulted in no measurable accumulation in the brain or other major tissue compartments. Possible mechanisms for TMPP-induced, short- and long-term, neurobehavioral modulation are discussed.     

Metabolism of N-ethyl-3-piperidyl benzilate in rats

The metabolic fate of N-ethyl-3-piperidyl benzilate (I) and its potential metabolites 3-piperidyl benzilate (II), N-ethyl-3-hydroxypiperidine (III), and 3-hydroxypiperidine (IV) was studied. Incubation of I with rat liver homogenates resulted in the formation of II and III. Only a trace of unchanged drug appeared in urine after intraperitoneal injection of I. Approximately 9% of the injected dose of I was excreted in urine as III and 2% in the form of metabolites that produced III after acid hydrolysis. After intraperitoneal injection of II in rats, 18% of the dose was excreted in urine as IV. Approximately 26% of the injected dose of III was present in urine as the unchanged drug, and 63% of the dose was excreted in the urine in the form of conjugates that produced III on acid hydrolysis. Urine of rats injected with IV contained approximately 50% of the injected dose as the unchanged drug and 50% of the dose in the form of a conjugate that produced IV on acid hydrolysis. The identity of the metabolites in extracts from urine was established by GLC-mass spectrometry. It is concluded that hydrolysis was one metabolic pathway for I and II. The major routes of elimination of these compounds are not yet known and may include excretion in feces or metabolic transformations resulting in the degradation of the piperidine ring.     

Integrated physical and transcript map of 5q31.3-qter

The disposition of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (CAS 155680-07-2, S-MTPPA, code: M-5011) was studied after oral administration to rats, dogs and monkeys using the 14C-labeled drug. After oral dosing, S-MTPPA was well absorbed from the gastrointestinal tract, to the extent of 97.7% in rats. The concentration of S-MTPPA in rat plasma reached a peak (Cmax: 13.07 micrograms/ml) at 15 min (tmax) after dosing and declined with a half-life (t1/2) of 2.5 h. The values of the parameters tmax, Cmax and t1/2 for dogs were 30 min, 26.2 micrograms/ml and 7.0 h, and those for monkeys were 15 min, 12.8 micrograms/ml and 3.0 h, respectively. The radioactivity was widely distributed in tissues and almost completely excreted in urine and feces within 48 h after oral administration to rats. The excretion of radioactivity in bile, urine and feces within 48 h after oral administration of 14C-S-MTPPA to bile duct-cannulated rats amounted to 75.0, 18.6 and 1.4% of the dose, respectively. The drug was metabolized mainly by oxidation of the thiophenyl moiety and by glucuronidation of the carboxyl group in rats and monkeys. The major urinary and fecal metabolite in dogs was identified as the taurine conjugate of MTPPA.     

Biliary excretion of furosemide glucuronide in rabbits

Furosemide (F) was administered to rabbits intravenously and intraduodenaly and the biliary excretion was studied. The major metabolite excreted in bile was furosemide glucuronide (FG). F and acyl migration isomers of FG (FG-iso) were also excreted in bile. The biliary excretion rates of total F (F+FG+FG-iso) following intraduodenal administration of F were much smaller than those following intravenous administration. The fraction of (F+FG-iso) in bile following intraduodenal administration of F were larger than those following intravenous administration. Stability of FG or FG-iso in bile and supernatant solution of the duodenum homogenate of rabbits was studied. FG was unstable in both media and its degradation followed apparent first-order kinetics in both media. In bile, FG degraded to produce several FG-iso and F, while in the supernatant solution of the duodenum homogenate, it hydrolyzed immediately to F. FG-iso were hardly detected in the supernatant solution. These results indicated that FG excreted in bile degraded easily to FG-iso and F. FG might easily hydrolyze to F enzymatically in the duodenum, and the resultant F might be reabsorbed from the intestinal tract. Unabsorbed FG-iso and F might be excreted in the feces.     

Reconstitution of cutaneous neural-immunological networks following bone marrow transplantation

Examination was made of the urinary and biliary excretion of the metabolites of genistein and genistein, the major components of Glycine and Sophora genus in rats. The urine of rats administered genistein orally contained eight metabolites. Three of these metabolites, genistein 4'-O-sulfate (M-1), genistein 7-O-beta-D-glucuronide (M-3), genistein 4'-O-sulfate 7-O-beta-D-glucuronide (M-6), were identified from spectroscopic and chemical data. The bile of rats administered genistein orally contained M-2, M-3 and M-6. M-6, a major biliary metabolite, was isolated and identified from spectroscopic and chemical data. The urine or bile of rats treated with genistein, the glycoside of genistein, contained M-1-M-8 or M-2, M-3, M-6 in the above metabolites. These findings suggest that genistein is absorbed as genistein after hydrolysis in the gastrointestinal tract. The total cumulative amounts of the two metabolites and genistein excreted in the urine during 48h, or of M-6 excreted in the bile during 36h following the oral administration of genistein, were approximately 5.7% or 16.0% of the doses administered, respectively. The result show that M-1, M-3 and M-6, having a free hydroxyl, glucuronide- or sulfate-conjugated hydroxyls at the C-7 or C-4' position, are excreted in the urine and bile as parts of the metabolites of genistein.     

Fecal bile acids and neutral sterols in patients with familial polyposis

Fecal neutral steroids and bile acids were measured in patients with familial polyposis, family controls who are immediate relatives of patients, and controls other than relatives. All subjects were consuming a mixed Western diet at the time of collection of stool specimens. Although the total fecal neutral sterol concentrations were not different between the groups, the patients with familial polyposis excreted a high amount of cholesterol and low levels of coprostanol and coprostanone compared with other groups. Patients with familial polyposis excreted levels of total bile acids in their feces comparable to those excreted by controls; lithocholic acid excretion was decreased in patients with familial polyposis. These findings suggest that analysis of stools for cholesterol and its metabolites be useful in screening the siblings of polyposis families for latent disease.     

Plasma, urinary and biliary residues in cattle following intramuscular injection of nortestosterone laurate

The synthetic androgen 19-nortestosterone (beta-NT) has been used illegally as a growth promoter in cattle production in the European Union. Elimination of beta-NT and its metabolites in plasma, urine and bile was studied in three cattle with cannulated gallbladders following intramuscular injection at a single site of 500 mg of the laurate ester (NTL) containing 300.5 mg beta-NT. Using enzyme immunoassay quantification, plasma Cmax of free beta-NT was 0.5 +/- 0.15 microgram/L (mean +/- SEM). Concentrations of free beta-NT in plasma were consistently greater than the assay limit of quantification (0.12 microgram/L) for 32.7 +/- 13.42 days. Mean residence time for the beta-NT in plasma was 68.5 +/- 20.75 days. Following sample preparation by immunoaffinity chromatography, high-resolution GC-MS was used to quantify beta-NT and alpha-NT in urine and bile. beta-NT was detected irregularly in urine from two of the three animals post injection. The principal metabolite present in the urine, alpha-NT, was detected for 160.3 +/- 22.67 days post injection. Cmax for alpha-NT in urine was 13.7 +/- 5.14 micrograms/L. Mean urinary AUC0-183 days for alpha-NT was 845.7 +/- 400.90 (microgram h)/L. In bile, alpha-NT was the only metabolite detected for 174.3 +/- 8.67 days post treatment. Cmax for alpha-NT in bile was 40.8 +/- 12.70 micrograms/L and mean biliary AUC0-183 days for alpha-NT was 1982.6 +/- 373.81 (microgram h)/L. Concentrations of alpha-NT in bile samples were greater than those in urine samples taken at the same time. The mean ratio of biliary:urinary AUC0-183 days was 3.0 +/- 0.72. It is concluded that bile is a superior fluid for detection of alpha-NT following injection of NTL, owing to the longer period during which residues may be detected after administration.     

Comparative studies of metabolism of simultaneously administered chenodeoxycholic acid and ursodeoxycholic acid in hamsters

We present the comparative studies of metabolism of chenodeoxycholic acid and ursodeoxycholic acid and their taurine conjugates in the liver and fecal culture from hamsters. When [24-14C]chenodeoxycholic acid and [11,12-3H]ursodeoxycholic acid were simultaneously instilled into the jujunal loop of bile fistula hamsters, both bile acids administered were recovered mainly as their conjugates with taurine and glycine in the fistula bile. The recovery of chenodeoxycholic acid was slightly but significantly higher than that of ursodeoxycholic acid. Chenodeoxycholic acid was more efficiently conjugated with glycine than ursodeoxycholic acid. The glycine/taurine ratio in the biliary chenodeoxycholic acid was 1.9, and that in ursodeoxycholic acid was 1.6. In addition, as much as 6.2% of ursodeoxycholic acid was excreted as the unconjugated form; on the other hand only 2.4% of unconjugated chenodeoxycholic acid was excreted. When [24-14C]chenodeoxycholyltaurine and [11,12-3H]ursodeoxycholyltaurine were simultaneously administered into the ileum loop of bile fistula hamsters, both bile salts were absorbed and secreted efficiently into the bile at the same rate. These results indicate that slightly lower recovery of ursodeoxycholic acid in the bile could be due to the less effective conjugation of ursodeoxycholic acid than chenodeoxycholic acid in the liver. Deconjugation by fecal culture from a hamster proceeded more rapidly in chenodeoxycholyltaurine than ursodeoxycholyltaurine. 7-Dehyroxylation to form lithocholic acid by fecal culture was also faster in chenodeoxycholic acid than ursodeoxycholic acid. The formation of 7-oxolithocholic acid from ursodeoxycholic acid was lesser than from chenodeoxycholic acid. In summary, bacterial deconjugation followed by 7-dehydroxylation to form lithocholic acid seems to be achieved more efficiently with chenodeoxycholic acid than ursodeoxycholic acid.     

Metabolism and disposition of 14C-granisetron in rat, dog and man after intravenous and oral dosing

1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0.25 and 5 mg/kg in rat and 0.25 and 10 mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man. 4. In rat and dog, 35-41% of the dose was excreted in urine and 52-62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5-25% of dose). 5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.     

The cell surface of Trypanosoma musculi bloodstream forms. II. Lectin and immunologic studies

Report is given on a metabolic investigation with non-radioactive and 14C-labelled methiothepin(1-[10',11'-dihydro-8'-(methylthio)-dibenzo mean value of b,f thiepin-10'yl]-4-methyl-piperazine) in rat, dog, and man. After i.p. and oral administration of the drug to the rat, the metabolites of methiothepin were excreted fecally. In the same species, a considerable biliary secretion of the compounds has been demonstrated. In dog and in man, excreted metabolites have been found both in urine and feces after oral application of the drug. The biotransformation of methiothepin within the species investigated proceeds via hydroxylation, sulfoxidation, O-methylation, N-demethylation, N-oxidation and formation of conjugates. The large number of metabolites is due to the various sites of action within the molecule, that are accessible to in vivo oxidation. Of a large number of isolated positionally isomeric compounds, merely the basal structures could be clarified. Possibly the mode of biotransformation to which methiothepin is subjected in the organism, proves determinant for the way of excretion. In the rat, all metabolites are hydroxylated and reach the intestinal tract as conjugates with the bile. In dog and man, however, non-hydroxylated, sulfoxidized metabolites were likewise found, which were excreted mainly renally in both species.     

Bioavailability, multiple-dose pharmacokinetics, and biotransformation of the aldose reductase inhibitor zopolrestat in dogs

Zopolrestat (Alond) is a new drug that is being evaluated as an aldose reductase inhibitor for the treatment of diabetic complications. The bioavailability in dogs of a 2 mg/kg oral dose of zopolrestat was 97.2%. In a 1-year, multiple-dose, pharmacokinetic study, systemic exposure increased with increasing dose (50, 100, and 200 mg/kg/day), and there were no consistent changes in exposure with multiple dosing. Renal clearance at 1 year appeared to be higher in males. The magnitude of the potential gender difference in exposure was relatively small and was unlikely to have had a meaningful impact on the pharmacokinetics of zopolrestat in dogs. In studies with bile duct-cannulated dogs, radioactivity from [14C]zopolrestat was primarily eliminated as unchanged drug and acyl glucuronide in the bile and feces (77.3% of the dose) and in urine (18.3% of the dose). The concentrations of acyl glucuronide in urine and feces were approximately 50% of the zopolrestat concentrations. Minor metabolites (each accounting for <1% of the dose) included those resulting from hydroxylation of the phthalazinone ring and glutathione conjugation of the benzothiazole ring.     

Metabolism of Ro 21-5998 (mefloquine) in the rat (author's transl)

After administration of 15 mg/kg 14C-Ro 21-5998/001 i.p. to rats, the metabolite patterns in feces, urine, bile and blood were compared. Metabolites from feces were identified by GC/MS, in all other cases by TLC. The main component in the feces consists of mefloquine (Ro 21-5998). In addition the acid Ro 21-5104, a derivative of mefloquine with a hydroxy group in the piperidine moiety (M 12), the alcohol Ro 14-0518 and a metabolite (M 4a), which is supposed to be a lactam, were shown to be present. The acid Ro 21-5104 is the main metabolite in the urine. The bile contains the parent compound Ro 21-5998, the acid Ro 21-5104 and the alcohol Ro 14-0518, partially as conjugates. The structurally investigated components account for about 40% of the administered dose. The blood contains the parent compound Ro 21-5998 and the acid Ro 21-5104 as main components. In comparing the various metabolite patterns, it can be summarized that that in urine is slightly different from those in bile (after hydrolysis of the conjugates), feces and blood which show more similarities between each other.     

Several properties of low-molecular weight tetanus antitoxin

Following intravenous injection of tetanus antitoxin, obtained by tryptic digestion of the horse immunoglobulin "Diaferm-3", purification and concentration of active fragments, the antitoxin was eliminated from the rabbit organism three times more rapidly than after the injection of the original "Diaferm-3" antitoxin. After injection of the split antitoxin its urinary excretion lasted up to 6 days, whereas following injection of the "Diaferm-3" antitoxin it was excreted for up to 19 days; in the first case considerably less antitoxin was excreted than in the second one (2 and 3.5%, respectively). In both cases in the antitoxin excreted with urine represented monovalent. Fab'-fragments, producing a delay in precipitation in the cross reaction in agar gel between the tetanus toxoid and the tetanus antiserum. Fab'-fragment obtained by the mentioned method possessed anaphylactogenic properties.     

Distribution and excretion of radiolabeled temoporfin in a murine tumor model

The biodistribution and excretion of temoporfin (tetra[m-hydroxyphenyl]chlorin, m-THPC), a recently developed photosensitizer, was investigated in BALB/c mice. [14C]temoporfin was administered intravenously (0.73 mumol/kg) to tumor-free mice or to mice implanted with the Colo 26 colorectal carcinoma. Blood, tissue and fecal samples were collected for 35 days and 10 days postdose from tumor-free mice and tumor-bearing mice, respectively. Blood concentrations fell rapidly such that at later time points they were indistinguishable from background counts. Tumor concentrations rose to a peak of 0.34 microgram temoporfin equivalents/mL at 2 days and then declined in parallel (log plot) with the blood concentrations. Tumor: tissue ratios at 2 days for skin, adipose tissue and skeletal muscle underlying the tumor were 1.5, 2.3 and 3.8, respectively. By 4 days the corresponding values were 1.6, 3.4 and 4.0. Nearly 40% of the administered radioactivity was excreted in the feces in the first 24 h and more than 80% had been excreted by 20 days. Less than 0.2% of the dose was recovered from the urine. An elimination half-life of 10-12 days was calculated from the excretion data.