Metabolism of furametpyr. 2. (14)C excretion, (14)C concentrations in tissues, and amounts of metabolites in rats

14C-Labeled furametpyr [N-(1,3-dihydro-1,1, 3-trimethylisobenzofuran-4-yl)-5-chloro-1, 3-dimethylpyrazole-4-carboxamide, Limber] was dosed to male and female rats at 1 (low dose) and 200 or 300 mg/kg (high dose). Elimination of furametpyr was rapid, and the dosed (14)C was substantially excreted within 7 days (45.5-53.3% in feces, 44.1-53. 8% in urine, and 0.01% in expired air). However, (14)C excretion rate showed sex- and dose-related differences, more rapid in males at low dose. (14)C concentrations in tissues decreased rapidly to generally low levels at 7 days (<0.004 ppm with the low dose and <1. 1 ppm with the high dose). Forty metabolites were detected, and 13 metabolites and 4 glucuronides were identified. A small amount of unchanged furametpyr was detected in feces (0.1-0.5% of the dose). The major metabolites in tissues were N-demethylated metabolites. In a bile study, 52.5-54.2% of the dosed (14)C was rapidly excreted into bile within 2 days. The absorption ratio was estimated to be >93.7% for the low dose (1 mg/kg). Major metabolites in bile were glucuronic acid conjugates of furametpyr hydroxides. On the basis of the results, furametpyr is substantially absorbed from the gastrointestinal tract after oral administration, rapidly distributed to tissues, extensively metabolized, and excreted into urine and bile or feces.     

Intestinal absorption of luteolin from peanut hull extract is more efficient than that from individual pure luteolin

Luteoin is one of the main flavones and the crucial effective component of peanut hull extract (PHE). The present paper aims to elucidate the absorption mechanism of luteolin and clarify whether its absorption occurs primarily at a specific site of the intestine by an in situ single-pass intestinal perfusion (SPIP) model. Moreover, the paper investigates the difference in absorption of luteolin when it is administered in PHE form and as pure luteolin by the SPIP model and in vivo pharmacokinetics studies. Results showed that the effective permeability ( P eff) and absorption rate constant ( k a) of pure luteolin(5.0 microg/mL) in duodenum and jejunum were not significantly different, but markedly higher than that in the colon and ileum. The P eff and k a of luteolin in jejunum were concentration-independent, and the ATP inhibitor (DNP) did not influence P eff and k a of pure luteolin. However, the P eff and k a of luteolin in PHE were significantly greater than that of pure luteolin. The pharmacokinetics study showed that following oral administration of a single dose of pure luteolin (14.3 mg/kg) or PHE (= 14.3 mg/kg of luteolin) in rats, the peak concentration of luteolin in plasma ( C max) and the area under the concentration curve (AUC) for pure luteolin were 1.97 +/- 0.15 microg/mL and 10.7 +/- 2.2 microg/mL.h, respectively. These parameters were significantly lower than those of the PHE group ( P < 0.05), C max = 8.34 +/- 0.98 microg/mL and AUC = 20.3 +/- 1.3 microg/mL.h, respectively. It can be concluded that luteolin is absorbed passively in the intestine of rats and that its absorption is more efficient in the jejunum and duodenum than in the colon and ileum. The bioavailability of luteolin in PHE form is significantly greater than that of pure luteolin.     

Disposition and metabolic profiling of bisphenol F in pregnant and nonpregnant rats

The distribution of bisphenol F (4,4'-dihydroxydiphenyl-methane, BPF) was studied in female Sprague-Dawley rats. Pregnant and nonpregnant animals were gavaged with a single dose of 7 or 100 mg/kg [3H]BPF and were kept for 96 h in metabolic cages. The excretion of BPF residues occurred mainly in urine (43-54% of the administered dose), which was found to contain at least six different metabolites, and to a lesser extent in feces (15-20% of the administered dose). Sulfatase treatment and subsequent high-performance liquid chromatography analyses suggest that the major urinary metabolite (more than 50% of the radioactivity present in urine) is a sulfate conjugate of BPF. At 96 h, BPF residues were detectable in all tissues examined with the largest amounts in the liver (0.5% of the dose). In pregnant rats dosed at day 17 of gestation, BPF residues were detected in the uterus, placenta, amniotic fluid, and fetuses (0.9-1.3% of the administered dose). Large amounts of radioactivity (8-10% of the dose) were still located in the digestive tract lumen at the end of the study. After administration of a single oral dose of [3H]BPF, 46% of the distributed radioactivity was excreted in bile over a 6 h period. In rats, BPF and/or its metabolites very likely undergo enterohepatic cycling, which could be responsible for the relatively high amounts of residues still excreted 4 days after BPF administration. This bisphenol is efficiently absorbed and distributed to the reproductive tract in female rats, and its residues pass the placental barrier at a late stage of gestation in rats.     

Ingested delphinidin-3-rutinoside is primarily excreted to urine as the intact form and to bile as the methylated form in rats

Many reports have described the bioavailability of anthocyanins; however, most of these reports investigated only the amount of anthocyanins excreted in urine. In the present study, we calculated the pharmacokinetic bioavailability of anthocyanins in rats by measuring the plasma concentration of delphinidin-3-rutinoside that had been administered orally or intravenously. Delphinidin-3-rutinoside was primarily absorbed in the blood and excreted into urine as unmetabolized forms with a T(max) of 26.3 min and a C(max) of 0.285 +/- 0.071 micromol/L. We detected small amounts of the metabolite 4'-O-methyl-delphinidin-3-rutinoside in the plasma, but we detected neither anthocyanidin (aglycone) nor glucuro- or sulfoconjugates. For the 8 h period after intake, delphinidin-3-rutinoside and 4'-O-methyl-delphinidin-3-rutinoside were excreted to urine at 795 +/- 375 and 12.3 +/- 2.91 nmol, respectively. Relative to intravenous injection, oral administration of delphinidin-3-rutinoside resulted in complete bioavailability (0.49 +/- 0.06%). Analysis of delphinidin-3-rutinoside plasma concentrations in bile cannulated rats revealed that, for the 8-h period after intake, the intact delphinidin-3-rutinoside excretion ratio in bile was 11% of the excretion ratio of 4'-O-methyl-delphinidin-3-rutinoside, 1.91 +/- 0.35 nmol versus 17.4 +/- 8.67 nmol, respectively. Setting the bile duct cannulation in a Bollman-type cage, however, significantly increased the bioavailability of orally administered delphinidin-3-rutinoside (18.14 +/- 6.24%). This effect appears to stem immobilization stress by reducing gastrointestinal motility. The cumulative excretion of delphinidin-3-rutinoside and 4'-O-methyl-delphinidin-3-rutinoside in urine and bile was 2.67 +/- 1.24% (w/w) of the dose ingested. Studies report that several metabolites are formed after oral ingestion of anthocyanins. Examples include glucuronyl from cyanidin-3-glucoside and both glucuronyl and sulfate conjugates from pelargonidin-3-glucoside. Our results indicate that delphinidin-3-rutinoside might be metabolized differently from cyanidin-3-glucoside and pelargonidin-3-glucoside.     

Dose-dependent absorption, metabolism, and excretion of genistein in rats

Genistein (4',5,7-trihydroxyisoflavone), a naturally occurring phenolic compound, possesses well-known preventive activity in breast and prostate cancer, cardiovascular diseases, and postmenopausal problems. The aim of this study is to investigate the distribution and dose-dependent absorption, metabolism, and excretion of genistein in rats. Genistein was orally administered to rats at different doses. At various time intervals, blood, bile, and urine samples were collected and incubated with glucuronidase to hydrolyze the glucuronidated genistein. Genistein was detected by HPLC. High levels of glucuronidated genistein were detected in the plasma, bile, and urine after genistein administration. When genistein was administered to rats at 6.25, 12.5, and 50 mg x kg (-1) doses, the AUC (0- t) values for genistein were 23.5, 80.9, and 177.9 mg x min x L (-1); the oral absolute bioavailabilities were 21.9, 33.5, and 19.0%; the AUC (0- t) values of glucuronidated genistein were 173.8, 470.7, and 1721.2 mg x min x L (-1), respectively. The cumulative biliary excretion of genistein respective to each dose was 42.6 +/- 6.5, 75.2 +/- 18.9, and 126.6 +/- 34.8 microg; the cumulative biliary excretion of glucuronidated genistein was 108.5 +/- 35.2, 423.5 +/- 158.3, and 853.7 +/- 320.8 microg for each dose, respectively. The cumulative urinary excretion of genistein was 34.8 +/- 10.8, 187.3 +/- 67.0 and 213.6 +/- 30.6 microg for each dose, respectively; the cumulative levels of glucuronidated genistein excreted in the urine were 217.8 +/- 52.1, 583.1 +/- 106.9, and 1108.4 +/- 88.1 microg, respectively. These results indicated that at high doses absorption, biotransformation, and excretion of genistein occurred in a nonlinear dose-dependent manner. Therefore, the results of these pharmacokinetic studies raise important questions about the therapeutic significance of consuming large quantities of genistein, genistein analogues, or soy-based neutraceuticals.     

Metabolic fate of (-)-[4-(3)H]epigallocatechin gallate in rats after oral administration

After oral administration of [4-(3)H]EGCg to rats, the radioactivity in blood, major tissues, urine, and feces was measured over time. The radioactivity in blood and most tissues remained low for 4 h postdose, began to increase after 8 h, peaked at 24 h, and then decreased. Major urinary excretion of radioactivity occurred in the 8-24 h period, and the cumulative radioactivity excreted by 72 h was 32.1% of the dose. The radioactivity in the feces was 35.2% of the dose within 72 h postdose. In the case of rats pretreated with antibiotics (antibiotic-pretreated rats), the radioactivity levels of the blood and urine were definitely lower than those in rats not pretreated with antibiotics (normal rats). The radioactivity recovered in the antibiotic-pretreated rat urine was estimated to be only (1)/(100) of that in the normal rat urine. These results clearly demonstrated that the radioactivity detected in the blood and urine of normal rats mostly originated from degradation products of EGCg produced by intestinal bacteria. Furthermore, a main metabolite in the normal rats was purified and identified as 5-(5'-hydroxyphenyl)-gamma-valerolactone 3'-O-beta-glucuronide (M-2). In feces of the normal rats, EGC (40.8% of the fecal radioactivity) and 5-(3',5'-dihydroxyphenyl)-gamma-valerolactone (M-1, 16.8%) were detected. These results suggested that M-1 was absorbed in the body after degradation of EGCg by intestinal bacteria, yielding M-1 with EGC as an intermediate. Furthermore, M-2 was thought to be formed from M-1 in the intestinal mucosa and/or liver, then to enter the systemic circulation, and finally to be excreted in the urine. Taking into account all of the above findings, a possible metabolic route of EGCg orally administered to rats is proposed.     

Metabolic fate of 2,4-dichlorophenol and related plant residues in rats

This study compared the metabolic fate of [(14)C]-DCP, [(14)C]-residues from radish plants, and purified [(14)C]-DCP-(acetyl)glucose following oral administration in rats. A rapid excretion of radioactivity in urine occurred for [(14)C]-DCP, [(14)C]-DCP-(acetyl)glucose, and soluble residues, 69, 85, and 69% within 48 h, respectively. Radio-HPLC profiles of 0-24 h urine from rats fed [(14)C]-DCP and [(14)C]-DCP-(acetyl)glucose were close and qualitatively similar to those obtained from plant residues. No trace of native plant residues was detected under the study conditions. The structures of the two major peaks were identified by MS as the glucuronide and the sulfate conjugates of DCP. The characterization of a dehydrated glucuronide conjugate by MS and NMR of DCP was unusual. In contrast to soluble residues, bound residues were mainly excreted in feces, 90% within 48 h, whereas total residues were eliminated in both urine and feces. For total residues, the radioactivity in feces was higher than expected from the percentage of soluble and bound residues in radish plants. This result highlighted that less absorption took place when residues were present in the plant matrix as compared to plant-free residues and DCP.     

Pharmacokinetics of cycloalliin, an organosulfur compound found in garlic and onion, in rats

Cycloalliin, an organosulfur compound found in garlic and onion, has been reported to exert several biological activities and also to remain stable during storage and processing. In this study, we investigated the pharmacokinetics of cycloalliin in rats after intravenous or oral administration. Cycloalliin and its metabolite, (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid, in plasma, urine, feces, and organs was determined by a validated liquid chromatography-mass spectrometry method. When administered intravenously at 50 mg/kg, cycloalliin was rapidly eliminated from blood and excreted into urine, and its total recovery in urine was 97.8% +/- 1.3% in 48 h. After oral administration, cycloalliin appeared rapidly in plasma, with a tmax of 0.47 +/- 0.03 h at 25 mg/kg and 0.67 +/- 0.14 h at 50 mg/kg. Orally administered cycloalliin was distributed in heart, lung, liver, spleen, and especially kidney. The Cmax and AUC0-inf values of cycloalliin at 50 mg/kg were approximately 5 times those at 25 mg/kg. When administered orally at 50 mg/kg, cycloalliin was excreted into urine (17.6% +/- 4.2%) but not feces. However, the total fecal excretion of (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid was 67.3% +/- 5.9% (value corrected for cycloalliin equivalents). In addition, no (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid was detected in plasma (<0.1 microg/mL), and negligible amounts (1.0% +/- 0.3%) were excreted into urine. In in vitro experiments, cycloalliin was reduced to (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid during anaerobic incubation with cecal contents of rats. These data indicated that the low bioavailability (3.73% and 9.65% at 25 and 50 mg/kg, respectively) of cycloalliin was due mainly to reduction to (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid by the intestinal flora and also poor absorption in the upper gastrointestinal tract. These findings are helpful for understanding the biological effects of cycloalliin.     

Metabolism of 7-fluoro-6-(3,4,5,6-tetrahydrophthalimido)-4- (2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (S-53482) in rat. 1. Identification of a sulfonic acid type conjugate

To examine the metabolic fate of 7-fluoro-6-(3,4,5, 6-tetrahydrophthalimido)-4-(2-propynyl)-2H-1,4-benzoxazin-3( 4H)-one (S-53482), rats were given a single oral dose of [phenyl-(14)C]-S-53482 at 1 (low) or 100 (high) mg/kg. The radiocarbon was almost completely eliminated within 7 days after administration in both groups. (14)C recoveries (expressed as percentages relative to the dosed (14)C) in feces and urine were 56-72 and 31-43%, respectively, for the low dose and 78-85 and 13-23%, respectively, for the high dose. S-53482 and seven metabolites were identified in urine and feces. Six of them were purified by several chromatographic techniques and identified by spectroanalyses (NMR and MS). Alcohol derivatives and an acetoanilide derivative were isolated from urine. Three sulfonic acid conjugates having a sulfonic acid group incorporated into the double bond of the 3,4,5,6-tetrahydrophthalimide moiety were isolated from feces. On the basis of the metabolites identified in this study, the metabolic pathways of S-53482 in rats are proposed.     

The metabolic fate of purified glucoraphanin in F344 rats

Dietary broccoli is commonly eaten cooked, exposing individuals to intact glucoraphanin rather than to its hydrolysis product, the anticarcinogenic isothiocyanate sulforaphane, since cooking destroys the hydrolyzing enzyme myrosinase. There is little information on the absorption and metabolism of glucoraphanin, due partly to the lack of purified compound. In this study, glucoraphanin was purified from broccoli seed and 150 mumol/kg was administered to male F344 rats. Glucoraphanin (5% of an oral dose) was recovered intact in urine, showing that it is absorbed intact, and no glucoraphanin or metabolites were found in feces. Total urinary products accounted for 20 and 45% of oral and intraperitonneal doses, respectively, including sulforaphane N-acetyl cysteine conjugate (12.5 and 2%), free sulforaphane (0.65 and 0.77%), sulforaphane nitrile (2 and 1.4%), and erucin (0.1 and 0.1%), respectively. Both glucoraphanin and its reduced form glucoerucin were identified in bile following intravenous glucoraphanin administration. We conclude that orally administered glucoraphanin is absorbed intact, undergoes enterohepatic circulation, and is hydrolyzed in the gut in F344 rats.     

Absorption, disposition, metabolism, and excretion of [3-(14)C]caffeic acid in rats

Male Sprague-Dawley rats ingested 140 × 10(6) dpm of [3-(14)C]trans-caffeic acid, and over the ensuing 72 h period, body tissues, plasma, urine, and feces were collected and the overall levels of radioactivity determined. Where sufficient radioactivity had accumulated, samples were analyzed by HPLC with online radioactivity and tandem mass spectrometric detection. Nine labeled compounds were identified, the substrate and its cis isomer, 3'-O- and 4'-O-sulfates and glucuronides of caffeic acid, 4'-O-sulfates and glucuronides of ferulic acid, and isoferulic acid-4'-O-sulfate. Four unidentified metabolites were also detected. After passing down the gastrointestinal tract, the majority of the radiolabeled metabolites were excreted in urine with minimal accumulation in plasma. Only relatively small amounts of an unidentified (14)C-labeled metabolite were expelled in feces. There was little or no accumulation of radioactivity in body tissues, including the brain. The overall recovery of radioactivity 72 h after ingestion of [3-(14)C]caffeic acid was ～80% of intake.     

Absorption, uptake and tissue affinity of high-molecular-weight hyaluronan after oral administration in rats and dogs

The purpose of this study was to determine the absorption, distribution and excretion of (99m)technetium-labeled, high-molecular-weight hyaluronan (((99m)Tc-HA) and (99m)technetium pertechnetate ((99m)Tc-P) after single dose, oral administration to Wistar rats and Beagle dogs. A pilot study utilized (99m)Tc-HA alone, and a second confirmatory study compared uptake of labeled (99m)Tc-HA with (99m)Tc-P. Urinary and fecal excretion after (99m)Tc-HA ingestion by rats showed 86.7-95.6% of radioactivity was recovered, almost all in feces. All tissues examined showed incorporation of radioactivity from (99m)Tc-HA starting at 15 min and persisting for 48 h, in a pattern significantly different from (99m)Tc-P. Whole-body scintigraphs and close-ups of the ventral chest region showed nonalimentary radioactivity from (99m)Tc-HA concentrated in joints, vertebrae and salivary glands four hours after administration. Autoradiography of skin, bone and joint tissue pieces after 24 h showed incorporation of radioactivity from (99m)Tc-HA, but not from (99m)Tc-P. Conversely, absorption, distribution and excretion of (99m)Tc was completely different from (99m)Tc-HA, showing an expected pattern of rapid absorption and excretion in urine, with accumulation in thyroid glands, stomach, kidney and bladder. This report presents the first evidence for uptake and distribution to connective tissues of orally administered, high-molecular-weight HA.     

Tissue residues, metabolism, and excretion of radiolabeled sodium chlorate (Na[36Cl]O3) in rats

A novel preharvest technology that reduces certain pathogenic bacteria in the gastrointestinal tracts of food animals involves feeding an experimental sodium chlorate-containing product (ECP) to animals 24-72 h prior to slaughter. To determine the metabolism and disposition of the active ingredient in ECP, four male Sprague-Dawley (approximately 350 g) rats received a single oral dose of sodium [36Cl]chlorate (3.0 mg/kg body weight). Urine, feces, and respired air were collected for 72 h. Radiochlorine absorption was 88-95% of the administered dose, and the major excretory route was the urine. Parent chlorate was the major species of radiochlorine present in urine at 6 h (approximately 98%) but declined sharply by 48 h (approximately 10%); chloride was the only other species of radiochlorine detected. Except for carcass remains (4.6% of dose), skin (3.2%), and gastrointestinal tract (1.3%), remaining tissues contained relatively low quantities of radioactivity, and >98% of radiochlorine remaining in the liver, kidney, and skeletal muscle was chloride. Chlorite instability was demonstrated in rat urine and bovine urine. The previously reported presence of chlorite in excreta of chlorate-dosed rats was shown to be an artifact of the analytical methods employed. Results from this study indicate that chlorate is rapidly absorbed and reduced to chloride, but not chlorite, in rats.     

Oxidative metabolites of the mammalian lignans enterodiol and enterolactone in rat bile and urine

Recent studies have shown that the mammalian lignans enterodiol (END) and enterolactone (ENL) are biotransformed in vitro by hepatic microsomes from rats and humans to various metabolites carrying one additional hydroxy group either at the aromatic or at the aliphatic moiety. To clarify whether these metabolites are also formed in vivo, each lignan was administered intraduodenally at a dose of 10 mg/kg of bw to bile duct-catheterized female Wistar rats and the 6 h bile analyzed by HPLC and GC-MS. With END-dosed rats, three products of aromatic and two of aliphatic monohydroxylation were found, whereas six aromatic and five aliphatic monohydroxylated biliary metabolites were detected after administration of ENL. The metabolites hydroxylated at the aromatic rings were unequivocally identified by comparison with synthetic reference compounds. The structures of the in vivo metabolites arising from aliphatic hydroxylation could not be completely elucidated; they were identical with some of the formerly reported microsomal products according to GC retention times and mass spectra. Significant amounts of most of the metabolites of the mammalian lignans identified in bile were also found in the urine of female rats after oral administration of 10 mg/kg of bw END or ENL and in the urine of female and male Wistar rats after they had been fed a diet containing 5% flaxseed. Thus, the mammalian lignans END and ENL give rise to several hydroxylated metabolites in vivo, which may contribute to the biological effects of these important food constituents.     

Absorption, tissue distribution, excretion, and metabolism of clothianidin in rats

Absorption, distribution, excretion, and metabolism of clothianidin [(E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine] were investigated after a single oral administration of [nitroimino-(14)C]- or [thiazolyl-2-(14)C]clothianidin to male and female rats at a dose of 5 mg/kg of body weight (bw) (low dose) or 250 mg/kg of bw (high dose). The maximum concentration of carbon-14 in blood occurred 2 h after administration of the low oral dose for both labeled clothianidins, and then the concentration of carbon-14 in blood decreased with a half-life of 2.9-4.0 h. The orally administered carbon-14 was rapidly and extensively distributed to all tissues and organs within 2 h after administration, especially to the kidney and liver, but was rapidly and almost completely eliminated from all tissues and organs with no evidence of accumulation. The orally administered carbon-14 was almost completely excreted into urine and feces within 2 days after administration, and approximately 90% of the administered dose was excreted via urine. The major compound in excreta was clothianidin, accounting for >60% of the administered dose. The major metabolic reactions of clothianidin in rats were oxidative demethylation to form N-(2-chlorothiazol-5-ylmethyl)-N'-nitroguanidine and the cleavage of the carbon-nitrogen bond between the thiazolylmethyl moiety and the nitroguanidine moiety. The part of the molecule containing the nitroguanidine moiety was transformed mainly to N-methyl-N'-nitroguanidine, whereas the thiazol moiety was further metabolized to 2-(methylthio)thiazole-5-carboxylic acid. With the exception of the transiently delayed excretion of carbon-14 at the high-dose level, the rates of biokinetics, excretion, distribution, and metabolism of clothianidin were not markedly influenced by dose level and sex.     

Synthesis of (-)-[4-3H]epigallocatechin gallate and its metabolic fate in rats after intravenous administration

Because a great deal of attention has been focused on the metabolism of (-)-epigallocatechin gallate (EGCg), quantitative analysis of this compound is required. For this purpose we developed a method of chemical synthesis of [4-(3)H]EGCg. Synthesized [4-(3)H]EGCg showed 99.5% radiochemical purity and a specific activity of 13 Ci/mmol. To clarify the excretion route of EGCg, the radioactivity levels of bile and urine were quantified after intravenous administration of [4-(3)H]EGCg to bile-duct-cannulated rats. Results showed that the radioactivity of the bile sample excreted within 48 h accounted for 77.0% of the dose, whereas only 2.0% of the dose was recovered in the urine. The excretion ratio of bile to urine was calculated to be about 97:3. These results clearly showed that bile was the major excretion route of EGCg. Time-course analysis of the radioactivity in blood was also performed to estimate the pharmacokinetic parameters following intravenous administration of [4-(3)H]EGCg. In addition, EGCg metabolites excreted in the bile within 4 h after the intravenous dose of [4-(3)H]EGCg were analyzed by HPLC. The results showed that 4',4"-di-O-methyl-EGCg was present in the conjugated form and made up about 14.7% of the administered radioactivity.     

Toxicokinetics, recovery, and metabolism of metamitron in goat

Toxicokinetic behavior and metabolism studies of metamitron and its effect on the cytochrome P(450) content of liver microsomal pellet were carried out in black Bengal goats after a single oral administration at 278 mg kg(-1) and consecutive oral administration of 30 mg kg(-1) for 7 days. Metamitron was detected in the blood sample at 0.08 h (12.0 +/- 0.87 microg mL(-1)), maximum at 4 h (84.3 +/- 8.60 microg mL(-1)) and minimum (14.6 +/- 1.67 microg mL(-1)) at 36 h blood sample after a single oral administration. The absorption rate constant was 0.69 +/- 0.09 h(-1). The Vd(area) (2.00 +/- 0.08 L kg(-1)) and t(1/2)beta (8.98 +/- 0.70 h) values suggested wide distribution and long persistence of the compound in the body. The values of T approximately B (0.80 +/- 0.04), F(c) (0.55 +/- 0.01), Cl(B) (0.15 +/- 0.00 L kg(-1) h(-1)), and K(21) (0.41 +/- 0.03 h(-1)) suggested that metamitron retained in the blood compared to that in the tissue. Maximum concentration of metamitron residue was found in the adrenal gland followed by bile on day 4 of single oral administration. The higher Cl(R) compared to Cl(H) value indicated the excretion of the major portion (34-40%) through urine compared to feces (20-26%). Maximum concentrations of metamitron and its metabolite, deaminometamitron, were excreted through urine and feces at 48 and 24 h samples, respectively. The recovery of metamitron including its metabolite in terms of parent compound varied from 69.3 to 80.1%, of which contribution of metabolite in terms of parent compound varied from 53.1 to 63.0%. Repeated oral administration of metamitron at 30 mg kg(-1) for 7 days caused induction of the cytochrome P(450) content of liver microsomal pellet of goat, suggesting oxidative deamination of metamitron.     

Pharmacokinetics and distribution of [35S]methylsulfonylmethane following oral administration to rats

Methylsulfonylmethane (MSM) is a sulfur-containing compound found in a wide range of human foods including fruits, vegetables, grains, and beverages. More recently, it has been marketed as a dietary supplement worldwide. The objective of this study was to evaluate the pharmacokinetic profile and distribution of radiolabeled MSM in rats. Male Sprague-Dawley rats were administered a single oral dose of [35S]MSM (500 mg/kg), and blood levels of radioactivity were determined at different time points for up to 48 h. Tissue levels of radioactivity at 48 and 120 h and urine and fecal radioactivity levels were measured at different time points for up to 120 h following [35S]MSM administration to rats. Oral [35S]MSM was rapidly and efficiently absorbed with a mean tmax of 2.1 h, Cmax of 622 microg equiv/mL, and AUC0-inf of 15124 h.microg equiv/mL. The t1/2 was 12.2 h. Soft tissue distribution of radioactivity indicated a fairly homogeneous distribution throughout the body with relatively lower concentrations in skin and bone. Approximately 85.8% of the dose was recovered in the urine after 120 h, whereas only 3% was found in the feces. No quantifiable levels of radioactivity were found in any tissues after 120 h, indicating complete elimination of [35S]MSM. The results of this study suggest that [35S]MSM is rapidly absorbed, well distributed, and completely excreted from the body.     

Phenolic antioxidants richly contained in corn bran are slightly bioavailable in rats

Phenolic acids (PAs) have been shown to be beneficial to human health and are found most abundantly in corn bran ( approximately 4%, w/w), one of the main dietary fibers. This study therefore evaluated the bioavailabilities of phenolic antioxidants ferulic acid (FA) and p-coumaric acid (PCA) in refined corn bran (RCB) by determining their recovery in the plasma, urine, and feces of rats fed a single meal of a RCB diet containing 5% RCB or adapted to the RCB diet for 10 days. In both studies, 0.4-0.5% of ingested FA and 1.2-2.3% of ingested PCA were recovered in rat urine. By contrast, approximately 81% of FA and approximately 64% of PCA ingested with the single meal were excreted through the rat feces within 3 days after the ingestion. On the other hand, after rats were fed the RCB diet, total FA (all forms of FA) was recovered in plasma at a concentration of 35.0 +/- 2.0 microg/L, total FA and total PCA were excreted through urine at levels of 155.4 +/- 5.8 and 50.9 +/- 6.6 microg/day, respectively. These parameters showed no significant change (P = 0.93, 0.09, and 0.66, respectively) after rats were fed the RCB diet continuously for up to 10 days. These results suggest that the PAs in RCB are bioavailable in rats. Their bioavailabilities, however, are relatively low compared with their high content in RCB and not improved by the adaptation for 10 days to the enriched RCB diet. Additionally, comparison with the results of other studies revealed that high contents of FA and, especially, diferulic acids in cereal bran, which act as cross-links between bran cell wall polysaccharides, may not improve but, rather, limit the bioavailabilities of PAs in vivo.     

Metabolism of metamitron in goat following a single oral administration of a nontoxic dose level: a continued study

Disposition kinetic behavior and metabolism studies of metamitron and its metabolite in terms of the parent compound were carried out in black Bengal goats after a single oral administration of a nontoxic oral dose at 30 mg kg(-1) of body weight. Metamitron was detected in the blood sample at 5 min (2.23 +/- 0.04 microg mL(-1)), maximum at 1 h (3.43 +/- 0.02 microg mL(-1)) and minimum at 12 h (0.41 +/- 0.01 microg mL(-1)), after a single oral administration. Metabolite [3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one] in terms of the parent compound was detected in the blood sample at 5 min (0.47 +/- 0.006 microg mL(-1)), maximum at 6 h (5.12 +/- 0.02 microg mL(-1)) and minimum at 96 h (1.06 +/- 0.016 microg mL(-1)), after a single oral administration. The t(1/2 K) and Cl(B) values of metamitron were 3.63 +/- 0.05 h and 1.36 +/- 0.016 L kg(-1) h(-1), respectively, whereas the t(1/2K)(m) and Cl(B)(m) values of the metabolite were 38.15 +/- 0.37 h and 0.091 +/- 0.001 L kg(-1) h(-1), respectively, which suggested long persistence of the metabolite in blood and tissues of goat. Metamitron was excreted through feces and urine for up to 48 and 72 h, whereas the metabolite was excreted for up to 168 and 144 h, respectively. Metabolite alone contributed to 96 and 67% of combined recovery percentage of metamitron and metabolite against the administered dose in feces and urine of goat, respectively. All of the goat tissues except lung, adrenal gland, ovary, testis, and mammary gland retained the metabolite residue for up to 6 days after administration.