Carcinogenicity assessment of lonidamine by dietary administration to Sprague-Dawley rats.

Following chronic dietary administration of 20, 60 and 180 mg/kg per day of lonidamine for 2 years to groups of Sprague-Dawley rats, treatment-related non-tumour findings seen microscopically included the following: atrophy of the testis with associated changes in epididymis and pituitary at all dosages; neuropathy in the sciatic nerve accompanied by skeletal muscle atrophy which was dose-related, particularly in male animals. Neither the incidence of tumour-bearing animals, nor the spectrum of tumours seen, was significantly changed. In the females given 180 mg/kg per day an overall reduction in tumour incidence was noted, which was reflected in a significant reduction (P < 0.001) in mammary tumours.     

Metabolism and disposition of 1-bromopropane in rats and mice following inhalation or intravenous administration

Workplace exposure to 1-bromopropane (1-BrP) can potentially occur during its use in spray adhesives, fats, waxes, and resins. 1-BrP may be used to replace ozone depleting solvents, resulting in an increase in its annual production in the US, which currently exceeds 1 million pounds. The potential for human exposure to 1-BrP and the reports of adverse effects associated with potential occupational exposure to high levels of 1-BrP have increased the need for the development of biomarkers of exposure and an improved understanding of 1-BrP metabolism and disposition. In this study, the factors influencing the disposition and biotransformation of 1-BrP were examined in male F344 rats and B6C3F1 mice following inhalation exposure (800 ppm) or intravenous administration (5, 20, and 100 mg/kg). [1,2,3-(13)C]1-BrP and [1-(14)C]1-BrP were administered to enable characterization of urinary metabolites using NMR spectroscopy, LC-MS/MS, and HPLC coupled radiochromatography. Exhaled breath volatile organic chemicals (VOC), exhaled CO(2), urine, feces, and tissues were collected for up to 48 h post-administration for determination of radioactivity distribution. Rats and mice exhaled a majority of the administered dose as either VOC (40-72%) or (14)CO(2) (10-30%). For rats, but not mice, the percentage of the dose exhaled as VOC increased between the mid ( approximately 50%) and high ( approximately 71%) dose groups; while the percentage of the dose exhaled as (14)CO(2) decreased (19 to 10%). The molar ratio of exhaled (14)CO(2) to total released bromide, which decreased as dose increased, demonstrated that the proportion of 1-BrP metabolized via oxidation relative to pathways dependent on glutathione conjugation is inversely proportional to dose in the rat. [(14)C]1-BrP equivalents were recovered in urine (13-17%, rats; 14-23% mice), feces (<2%), or retained in the tissues and carcass (<6%) of rats and mice administered i.v. 5 to 100 mg/kg [(14)C]1-BrP. Metabolites characterized in urine of rats and mice include N-acetyl-S-propylcysteine, N-acetyl-3-(propylsulfinyl)alanine, N-acetyl-S-(2-hydroxypropyl)cysteine, 1-bromo-2-hydroxypropane-O-glucuronide, N-acetyl-S-(2-oxopropyl)cysteine, and N-acetyl-3-[(2-oxopropyl)sulfinyl]alanine. These metabolites may be formed following oxidation of 1-bromopropane to 1-bromo-2-propanol and bromoacetone and following subsequent glutathione conjugation with either of these compounds. Rats pretreated with 1-aminobenzotriazole (ABT), a potent inhibitor of P450 excreted less in urine (down 30%), exhaled as (14)CO2 (down 80%), or retained in liver (down 90%), with a concomitant increase in radioactivity expired as VOC (up 52%). Following ABT pretreatment, rat urinary metabolites were reduced in number from 10 to 1, N-acetyl-S-propylcysteine, which accounted for >90% of the total urinary radioactivity in ABT pretreated rats. Together, these data demonstrate a role for cytochrome P450 and glutathione in the dose-dependent metabolism and disposition of 1-BrP in the rat.     

Inhalation pharmacokinetics of 1,2-dichloroethane after different dietary pretreatments of male Sprague-Dawley rats

The effect of the pretreatment of male Sprague-Dawley rats with phenobarbital (PB), butylated hydroxyanisole (BHA) and disulfiram (DSF) on the inhalation kinetics of 1,2-dichloroethane [ethylene dichloride (EDC)] was studied by the gas uptake method. A closed recirculating system was constructed and characterized. The rate curves in all the pretreatment regimens showed saturable dependence on EDC concentration. These saturable dependencies (Michalis-Menten) appeared to be associated with enzymatic metabolism. In general, a two-compartment, steady-state pharmacokinetic model described the uptake data. Data were transformed by Hanes plots to calculate the inhalational K_m, the ambient EDC concentration at which uptake proceeded at half maximum rate, and V_max, the maximum rate of uptake (i. e., maximum rate of metabolism). Although PB and BHA pretreatments did not affect the K_m of EDC, PB pretreatment increased the V_max while DSF pretreatment decreased both the K_m and V_max.     

Mass spectrometric determination of p-nonylphenol metabolism and disposition following oral administration to Sprague-Dawley rats

Isomers of 4-nonylphenol (NP), which are important industrial compounds and environmental breakdown products from widely used surfactants, have estrogenic activity in vitro and in vivo that has prompted interest in its potential for modulation of endocrine function in humans and wildlife. Mass spectrometry was used to quantify NP and metabolites in serum and endocrine-responsive tissues from dietary exposure in Sprague-Dawley rats. Tissue accumulation of NP aglycone was observed despite the predominance of glucuronidation in blood. Serum toxicokinetics of total NP, measured following gavage administration, showed rapid absorption and elimination (average half-times 0.8 and 3.5 h, respectively). NP was similarly administered by gavage to pregnant dams and total and aglycone NP were measured in dam serum and fetuses to show placental transfer into serum and brain. These data provide a basis for future correlations of biologic effects observed following dietary exposure in rats with those predicted from environmental exposures to humans.     

Metabolism and disposition of hydroquinone in Fischer 344 rats after oral or dermal administration.

Studies were conducted to determine the absorption, tissue distribution, excretion, and metabolism of 14C-hydroquinone (HQ) in male and female rats following single oral, repeated oral, or 24-h dermal administration. The concentration of parent compound in blood was also determined following a single 50-mg/kg gavage administration. Absorption into the blood was rapid after oral dosing; the maximum concentration of parent compound was attained within 20 min after dosing, and the maximum concentration of total 14C was attained within 30 min. Parent compound represented 1% of total 14C in blood, indicative of extensive first-pass metabolism. Excretion was primarily via the urine within the first 8h of gavage. Typically, 87-94% of the 14C was excreted in urine. Dermal application of 14C-HQ (20 microCi) as a 5.4% aqueous solution resulted in near background levels of 14C in blood; the maximum mean blood concentration was 0.65 microg HQ equivalents/g in females and not quantifiable in males. The majority (61-71%) of the 14C was recovered from the skin surface by washing at 24 h. HQ was extensively metabolized following oral dosing with typically <3% of the dose excreted as parent compound. The major urinary metabolites of HQ were glucuronide and O-sulfate conjugates, which represented 45-53% and 19-33%, respectively, of an oral dose. A <5% metabolite was identified as a mercapturic acid conjugate of HQ.     

Metabolism and disposition of [(14)C]1-nitronaphthalene in male Sprague-Dawley rats.

In rats and mice, 1-nitronaphthalene (1-NN) produces both lung and liver toxicity. Even though these toxicities have been reported, the metabolism and disposition of 1-NN have not been elucidated. Therefore, studies were performed to characterize its fate after i.p. and i.v. administration to male Sprague-Dawley rats. After i.p. administration of [(14)C]1-NN (100 mg/kg; 60 microCi/kg), 84% of the dose was eliminated in the urine and feces by 48 h. At 96 h, 60% of the dose was recovered in the urine, 32% in the feces, and 1% collectively in the tissues, blood, and gastrointestinal contents. The terminal phase rate constant (k(term)) of 1-NN was 0.21 h(-1), the terminal phase half-life (T(1/2,term)) was 3.40 h, and the systemic bioavailability was 0.67. When administered i.v. (10 mg/kg; 120 microCi/kg), 85% of the dose was eliminated in the urine and feces by 24 h. At the end of the study (96 h), 56% of the dose was recovered in the urine, 36% in the feces, and 1% collectively in the tissues, blood, and gastrointestinal contents. Interestingly, 88% of the dose was secreted into bile by 8 h. The k(term) was 0.94 h(-1) and the T(1/2,term) was 0.77 h. The major urinary metabolite after both routes of administration was N-acetyl-S-(hydroxy-1-nitro-dihydronaphthalene)-L-cysteine. Other urinary metabolites identified include hydroxylated, dihydroxylated, glucuronidated, sulfated, and reduced metabolites, as well as dihydrodiol. The major biliary metabolite was hydroxy-glutathionyl-1-nitro-dihydronaphthalene. These data show that 1-NN undergoes extensive metabolism and enterohepatic recirculation, and the majority of the dose is eliminated in the urine.     

Corticosterone concentrations in blood and excretion in faeces after ACTH administration in male Sprague-Dawley rats

The aim of the present study was to analyse the corticosterone response to exogenous ACTH in the circulation of catheterised male rats and to investigate the sensitivity of faecal corticosterone output as a measure of preceding elevated levels in the circulation. A total of 21 adult male Sprague-Dawley rats permanently catheterised (v. jugularis externa for intravenous administration of ACTH and a. carotis communis for blood sampling), were used. Administration of both 10 and 100 microg/kg ACTH resulted in a rapid and pronounced corticosterone increase three minutes after injection (226 and 220 ng/ml, respectively), but the duration of the response was different. In the 10 microg/kg group, corticosterone levels were significantly elevated for 3-90 min after injection, while in the 100 microg/kg group, the levels remained elevated for 240 min after injection. In faeces, a significant increase during eight hours after ACTH injection was found in the group treated with 100 microg/kg, but not in the group treated with 10 microg/kg. In conclusion, quantification of faecal excretion of corticosteroids is a useful non-invasive measure of prior substantial stress (e.g. surgery), but not sufficiently sensitive to reveal minor stress or acute stress of short duration.     

Characterization of the disposition of lutein after i.v. administration to rats

Lutein is a carotenoid that has antioxidant effects. Although lutein has received much attention recently due to its antioxidant activities, little information about the pharmacokinetic properties of lutein is available. The disposition of lutein after i.v. administration has not been investigated because lutein is now used as a supplement. The present study was undertaken to acquire additional data on the disposition of lutein after i.v. administration. After i.v. administration, lutein is preferentially distributed to the liver, spleen and lung. Intravenous administration of lutein may provide effective antioxidant activities in these tissues, not only the eye. The results of this study should provide valuable data for drug development.     

The physiology and toxicology of acute inhalation phosphine poisoning in conscious male rats

Phosphine (PH₃) is a toxidrome-spanning chemical that is widely used as an insecticide and rodenticide. Exposure to PH₃ causes a host of target organ and systemic effects, including oxidative stress, cardiopulmonary toxicity, seizure-like activity and overall metabolic disturbance. A custom dynamic inhalation gas exposure system was designed for the whole-body exposure of conscious male Sprague-Dawley rats (250–350?g) to PH₃. An integrated plethysmography system was used to collect respiratory parameters in real-time before, during and after PH₃ exposure. At several time points post-exposure, rats were euthanized, and various organs were removed and analyzed to assess organ and systemic effects. The 24?h post-exposure LCt₅₀, determined by probit analysis, was 23,270?ppm?×?min (32,345?mg?×?min/m³). PH₃ exposure affects both pulmonary and cardiac function. Unlike typical pulmonary toxicants, PH₃ induced net increases in respiration during exposure. Gross observations of the heart and lungs of exposed rats suggested pulmonary and cardiac tissue damage, but histopathological examination showed little to no observable pathologic changes in those organs. Gene expression studies indicated alterations in inflammatory processes, metabolic function and cell signaling, with particular focus in cardiac tissue. Transmission electron microscopy examination of cardiac tissue revealed ultrastructural damage to both tissue and mitochondria. Altogether, these data reveal that in untreated, un-anesthetized rats, PH₃ inhalation induces acute cardiorespiratory toxicity and injury, leading to death and that it is characterized by a steep dose-response curve. Continued use of our interdisciplinary approach will permit more effective identification of therapeutic windows and development of rational medical countermeasures and countermeasure strategies.     

Toxicokinetics of 14C-endosulfan in male Sprague-Dawley rats following oral administration of single or repeated doses

Endosulfan (ES), an organochlorine (OC) insecticide that belongs to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. The toxicokinetics of 14C-endosulfan following oral administration of a single dose of 5 mg/kg body weight was investigated in male Sprague-Dawley rats. Three rats were sacrificed 30 min, 1 h, 2 h, 4 h, and 8 h after dosing. 14C-endosulfan radioactivity was detected in all tissues at each time point. In a separate experiment urine and feces were collected for 96 h. The total radioactivity recovered in the excreta for 4 days was 106.8% +/- 26.2%, with fecal elimination the major route of elimination route (94.4% +/- 21.4%). The cumulative excretion in the urine for 4 days was 12.4% +/- 4.8%. Radioactivity 8 h after administration was highest in gastrointestinal (GI) tract tissue (20.28 +/- 16.35 mg ES eq./L) and lowest in muscle (0.18 +/- 0.06 mg ES eq./L). The toxicokinetic parameters obtained from 14C-endosulfan-derived radioactivity in blood were distribution half-life (T1/2 x) = 31 min and terminal elimination half-life (T1/2 y) = 193 h. Blood concentration reached its maximum (Cmax) of 0.36 +/- 0.08 mg ES eq./L 2 h after the oral dose. Endosulfan was rapidly absorbed into the GI tract in rats, with an absorption rate constant (ka) of 3.07 h(-1).     

Induction of testosterone biotransformation enzymes following oral administration of methyl tert-butyl ether to male Sprague-Dawley rats.

Methyl tert-butyl ether (MTBE) is an oxygenated fuel additive used to decrease carbon monoxide emissions during gasoline combustion. In the current study, we investigated the hypothesis that the MTBE-induced decrease in serum testosterone levels in male rats may be due in part to the ability of MTBE to induce the metabolism of endogenous testosterone and hence enhance its clearance. Nine-week-old male Sprague-Dawley rats were gavaged with 250, 500, 1000, or 1500 mg MTBE/kg/day in corn oil or corn oil alone for 15 or 28 consecutive days. Increased relative liver weight (10-14%) and minimal-to-moderate centrilobular hypertrophy were observed in rats treated with 1000 and 1500 mg MTBE/kg/day (high doses) for 28 days. Total hepatic microsomal cytochrome P450 (CYP) was increased 1. 3-fold in the high-dose, 15-day-treated rats. An evaluation of specific CYP activities using selective markers demonstrated a 2. 0-fold increase in CYP2B1/2 in rats treated with 1000 mg MTBE/kg/day for 28 days, and with 1500 mg MTBE/kg/day for 15 and 28 days (6.5- and 2.9-fold, respectively). CYP1A1/2, CYP2A1, and CYP2E1 activities were increased 1.5-, 2.4-, and 2.3-fold, respectively, in high-dose, 15-day-treated rats. CYP2E1 was also increased in high-dose, 28-day-treated rats (2.0-fold). CYP3A1/2 was increased 2.1-fold and UDP-glucuronosyltransferase activity 1.7-fold in high-dose, 28-day-treated rats. MTBE also induced its own metabolism 2.1-fold in high-dose, 28-day-treated rats. Results indicate that MTBE induces selected enzymes involved in testosterone metabolism. The decrease in serum testosterone observed following MTBE administration may be the result of enhanced testosterone metabolism and subsequent clearance.     

Disposition of [14C]nonoxynol-9 after intravenous or vaginal administration to female Sprague-Dawley rats

The disposition of nonoxynol-9 labeled with carbon-14 at the ethylene oxide units was studied following an iv or vaginal administration to female Sprague-Dawley rats. The results from the vaginal administration studies indicate 12.8% absorption of 14C radioactivity in 6.0 hr and 37.7% in 24.0 hr. Tissue distribution studies showed that the small and large intestines, including their contents, had the highest 14C activity by either route of administration. Radiomonitored HPLC of bile collected at 6.0 hr and urine at 6.0, 24.0, and 48.0 hr following an iv injection of [14C]nonoxynol-9 showed that the compound was completely metabolized in the body of the rat. The metabolites were primarily excreted in the feces and secondarily in the urine. Analysis of urinary metabolites containing the carbon-14 label, 6.0 hr following an iv dose, indicated the presence of highly polar neutral (53.27%) and acidic (39.23%) species.     

Lack of hydroxylated fullerene toxicity after intravenous administration to female Sprague-Dawley rats

Hydroxylated fullerenes (C??OH(x)) or fullerols are water-soluble carbon nanoparticles that have been explored for potential therapeutic applications. This study assesses acute in vivo tolerance in 8-wk-old female Sprague-Dawley rats to intravenous (iv) administration of 10 mg/kg of well-characterized C??(OH)??. Complete histopathology and clinical chemistries are assessed at 8, 24, and 48 h after dosing. Minor histopathology changes are seen, primarily in one animal. No clinically significant chemistry changes were observed after treatment. These experiments suggest that this fullerol was well tolerated after iv administration to rats.     

Fate of n-butanol in rats after oral administration and its uptake by dogs after inhalation or skin application.

n-[1-¹⁴C]Butanol was mixed with corn oil and administered by gavage to male Charles River C.D. rats in doses of 4.5, 45, or 450 mg/kg of body wt. Rats dosed with 450 mg/kg excreted 83.3% of the dose as ¹⁴CO₂ at 24 hr; 4.4% was excreted in the urine; less than 1% was eliminated in feces and 12.3% remained in the carcass. n-[1-¹⁴C]Butanol was excreted in the urine apparently as an O-sulfate and as an O-glucuronide, both of which accounted for 75% of the radioactivity. Urea accounted for the remainder. Rats dosed with 4.5 or 45 mg/kg showed a similar excretion pattern to that of rats dosed with 450 mg/kg. Excretion studies were performed to quantify the percutaneous absorption of n-butanol in male beagle dogs. n-[1-¹⁴C]Butanol was absorbed through the skin of dogs at a rate of 8.8 μg min^?1 cm^?2. Dogs exposed by inhalation to 50 ppm of n-butanol vapor absorbed about 55% of the inhaled vapor. The elimination of n-butanol in the postexposure breath was relatively low compared to the quantity absorbed during the exposure. Dogs dosed with ethanol (200 mg/kg, po) and then exposed to 50 ppm of n-butanol vapor for 6 hr showed no evidence that the exposure to n-butanol vapor inhibited the metabolism of ethanol. These findings suggest that occupational exposure to n-butanol vapor at the current threshold limit value is not likely to affect the metabolism of low doses of ethanol taken concurrently.     

Simultaneous administration of diethylphthalate and ethyl alcohol and its toxicity in male Sprague-Dawley rats

Phthalate esters have been implicated as xenoestrogens. One among them is di-ethylphthalate (DEP), which is used as plasticizer, detergent base, and binder in incense sticks and after-shave lotions. DEP is one of the contaminants of freshwater and marine ecosystems. Incense stick workers are occupationally exposed to DEP and some workers are chronic alcoholics. Therefore, a study was undertaken to evaluate the interactive toxicity of DEP with ethyl alcohol (EtOH) in young male Sprague-Dawley rats. The rats were given 50 ppm DEP (w/v), 5% EtOH (v/v) and a combined dose of 50 ppm DEP (w/v)+EtOH (5% v/v) in water ad libitum for a period of 120 days and were maintained on normal diet. Control animals received normal diet and plain water. During the treatment rats were weighed every week and water consumption per day was measured. After the completion of treatment, liver weight/body weight, liver weight, body weight, serum enzymes and other biochemical parameters were assessed. It was found that there was no significant change observed in body weight, liver weight, liver weight/body weight and water consumption. It was observed that there was a significant decrease in liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in EtOH, DEP and EtOH+DEP treated rats in the order of EtOH>DEP>EtOH+DEP as compared with control. Serum AST, ALT, acid phosphatase (ACP), alkaline phosphatase (ALP), succinate dehydrogenase (SDH) and liver ACP showed significant increase in DEP and EtOH+DEP treated rats in the order of DEP>EtOH+DEP as compared with control and EtOH treated rats. On the contrary, there was no significant change in liver ALP levels in treated rats. There was significant increase in liver SDH, glycogen, total triglyceride, total cholesterol and lipid peroxidation in DEP and EtOH+DEP treated rats, but no significant changes in the serum SDH, glucose and total triglyceride levels. Serum total cholesterol levels in DEP and EtOH+DEP treated rats were significantly high as compared to control and EtOH treated rats. These results show that there is no interaction of DEP with EtOH but DEP alone leads to severe impairment of lipid metabolism coupled with toxic injury to the liver as evident from significantly altered lipid and enzyme levels in the liver and serum. Long term simultaneous exposure to DEP and EtOH may have severe implications for humans who are occupationally exposed to these two xenobiotics.     

Alterations in endocrine responses in male Sprague-Dawley rats following oral administration of methyl tert-butyl ether.

Methyl tert-butyl ether (MTBE) is an oxygenated fuel additive used to decrease carbon monoxide emissions during combustion. MTBE is a nongenotoxic chemical that induces Leydig cell tumors (LCT) in male rats. The mechanism of MTBE-induced LCT is not known; however, LCT induced by other nongenotoxic chemicals have been associated with the disruption of the hypothalamus-pituitary-testicular (HPT) axis. The objective of this study was to determine whether MTBE functions as an endocrine-active compound by affecting levels of specific hormones involved in the maintenance of the HPT axis. Nine-week-old male Sprague-Dawley rats were administered MTBE by gavage at 0, 250, 500, 1000, or 1500 mg MTBE/kg/day for 15 or 28 consecutive days and sacrificed 1 h following the last dose. Relative testis weights were increased only in high-dose animals treated for 28 days, and no testicular lesions were observed at any dose level. Adrenal gland, liver, and kidney weights were also increased. Histologic changes included protein droplet nephropathy of the kidney and centrilobular hypertrophy of the liver. Interstitial fluid and serum testosterone levels as well as serum prolactin levels were decreased only in animals treated with 1500 mg MTBE/kg/day for 15 days. At 28 days, serum triiodothyronine (T3) was significantly decreased at 1000 and 1500 mg MTBE/kg/day compared to control animals, and a decrease in serum luteinizing hormone and dihydrotestosterone was observed at 1500 mg MTBE/kg/day. These results indicate that MTBE causes mild perturbations in T3 and prolactin; however, the changes in testosterone and LH levels did not fit the pattern caused by known Leydig cell tumorigens.     

Fluoride ion excretion by male rats after inhalation of one of several fluoroethylenes or hexafluoropropene

Male rats were exposed to atmospheres containing various fluorinated ethylene derivatives or hexafluoropropene in sublethal concentrations. The increase in urinary fluoride after exposure to these fluorocarbon atmospheres suggested that they were biologically degraded to free fluoride ion. Inhalation of the fluorocarbon atmospheres also produced an increase in the urinary excretion of potassium ion and creatinine, and a diuresis which persisted for up to 2 weeks post-exposure. Hexafluoropropene was most effective in producing these effects and also caused a marked glucosuria for 3–4 days post-exposure. Histologically, hexafluoropropene also caused a frank necrosis of the proximal renal tubules. These studies suggest that the simple fluoroalkenes are biodegradable and that this can be demonstrated by the increased urinary excretion of free fluoride ion following exposure.     

Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats

Genistein is a naturally occurring isoflavone that interacts with estrogen receptors and multiple other molecular targets. Human exposure to genistein is predominantly through consumption of soy products, including soy-based infant formula and dietary supplements. A dose range-finding study was conducted as a prelude to a multigeneration bioassay to assess potential toxicities associated with genistein consumption. Genistein was administered in a soy- and alfalfa-free diet at 0, 5, 25, 100, 250, 625, or 1250 ppm to pregnant dams starting on Gestation day 7 and continuing throughout pregnancy. Dietary exposure of the dams continued through lactation, and pups were maintained on the same dosed feed as their mother after weaning until sacrifice at Postnatal day 50. Body weight and feed consumption of the treated dams prior to parturition showed a decreasing trend with a significant reduction at the highest dose. Litter birth weight was depressed in the 1250 ppm dose group, and pups of both sexes in that dose group had significantly decreased body weights relative to controls at the time of sacrifice. The most pronounced organ weight effects in the pups were decreased ventral prostate weight in males at the 1250 ppm dose and a trend toward higher pituitary gland to body weight ratios in both sexes. Histopathologic examination of female pups revealed ductal/alveolar hyperplasia of the mammary glands at 250 to 1250 ppm. Ductal/alveolar hyperplasia and hypertrophy also occurred in males, with significant effects seen at 25 ppm and above. Abnormal cellular maturation in the vagina was observed at 625 and 1250 ppm, and abnormal ovarian antral follicles were observed at 1250 ppm. In males, aberrant or delayed spermatogenesis in the seminiferous tubules relative to controls was observed at 1250 ppm. There was a deficit of sperm in the epididymis at 625 and 1250 ppm relative to controls, although testicular spermatid head counts and epididymal spermatozoa counts did not show significant differences from controls at these doses. Both sexes showed an increase in the incidence and/or severity of renal tubal mineralization at doses of 250 ppm and above. Dietary genistein thus produced effects in multiple estrogen-sensitive tissues in males and females that are generally consistent with its estrogenic activity. These effects occurred within exposure ranges achievable in humans.     

Metabolism and plasma pharmacokinetics of isoorientin,a natural active ingredient,in Sprague-Dawley male rats after oral and intravenous administration

Abstract

1. Several pharmacological effects have been revealed on isoorientin, suggesting its potential medicinal prospects. The metabolic and plasma pharmacokinetic profiles of isoorientin were investigated in rats.

2. For intra-gastric gavage, parent drug and three metabolites were detected in urine and feces by HPLC–MS/MS, but only one metabolite was found in plasma and identified as isoorientin 3′- or 4′-O-sulfate (M1) according to MS and UV absorbance spectra.

3. After a single i.v. administration of isoorientin (5, 10, or 15?mg/kg B.W.) in rats, linear pharmacokinetic property was observed with favorable terminal half-lives (1.67?±?1.32–2.07?±?0.50?h). After a single p.o. administration of isoorientin (150?mg/kg B.W.) in rats, plasma isoorientin concentration was low, but the concentration of M1 was comparatively high. Low systemic exposure of oral isoorientin in rats could result from its low aqueous solubility and extensive first-pass metabolism, and plasma concentration of M1 can be used as a biomarker of isoorientin intake. Isoorientin showed low oral bioavailability (8.98?±?1.07%), and had about 6% or 45% dose recovery in urine or feces, respectively, 72?h after intra-gastric gavage.

4. These studies are the first to describe the pharmacokinetics of isoorientin via i.v. or p.o. dosing, providing important information for understanding its process in vivo.