Some pharmacodynamic properties of carrageenin in the rat

1. Carrageenin oedema is suppressed by pre-treating the rats with cellulose sulphate, a kininogen depleting agent. This inhibition is closely related to the dose of cellulose sulphate and to the time course of kininogen depletion.2. Oedema induced by egg white or by dextran, in which the mediators are histamine and 5-hydroxytryptamine, is quite unaffected by cellulose sulphate treatment.3. Carrageenin injected intravenously lowers the arterial blood pressure of rats. This hypotensive effect is unaffected by histamine antagonists and is abolished by protease inhibitors and thus seems to be due to kinin release from plasma substrates.4. Like cellulose sulphate, carrageenin enhances the esterolytic activity of the blood from treated rats when incubated with benzoyl-arginine ethyl ester.5. The ability of carrageenin to activate the kinin-forming system could account for both its inflammatory and hypotensive effects.     

Fibrinolytic activity evoked in the plasma of the normal and adrenalectomized rat by cellulose sulphate

1. Cellulose sulphate, a kinin-releasing agent, produced fibrinolytic activity in plasma when administered intravenously to the rat but not when added to fresh rat plasma in vitro. The in vivo effect was maximal within 1 min and disappeared within 10-20 minutes. It was retained in plasma taken 1 min after the injection and kept at room temperature for 30 minutes.2. A decrease of anti-fibrinolytic potency measured against urokinase-activated bovine plasmin, was shown to occur in plasma of rats given cellulose sulphate.3. Activated rat plasma lysed heat-denatured fibrin: it probably contains free plasmin as well as plasminogen activator.4. Adrenalectomized rats did not exhibit fibrinolytic activity nor statistically significant benzoyl-arginine ethyl ester-esterase activation in plasma after cellulose sulphate treatment.5. Adrenalectomized rats had significantly increased levels of plasma kininogen, but were normally sensitive to the kininogen-depleting action of cellulose sulphate.6. The increased plasma kininogen of adrenalectomized rats seems to be a consequence of the impairment of the plasminogen activating mechanism.     

Feline endotoxin shock: effects of methylprednisolone on kininogen-depletion, on the pulmonary circulation and on survival.

1 Escherichia coli endotoxin, administered intravenously in a dose of 2 mg/kg to pentobarbitone anaesthetized, artificially ventilated cats resulted in pulmonary hypertension, systemic hypotension and an immediate (1-2 min) 30-40% reduction in plasma kininogen, an effect which probably indicates a release of plasma kinins. 2 Methylprednisolone (30 mg/kg), when administered 30 min before endotoxin, did not influence the endotoxin-induced pulmonary hypertension or systemic hypotension but completely prevented the depletion of plasma kininogen. 3 In spontaneously breathing cats, methylprednisolone, administered 30 min after endotoxin, caused a rapid repletion of kininogen and prolonged survival (47% at 6 h compared to 10% in the endotoxinalone animals). Methylprednisolone did not appear to influence lactate production or the hyperventilation observed during the delayed endotoxin shock phase. 4 It is concluded t,at methylprednisolone does not prevent the release, by endotoxin, of a pulmonary vasoconstrictor prostaglandin, or its effects, but that perhaps by preventing kinin release it may reduce endotoxin-induced capillary leakage.     

In vivo effects of cellulose sulphate on plasma kininogen, complement and inflammation

1. The in vivo action of cellulose sulphate was studied in an attempt to clarify the role of complement and kinin formation in inflammation.2. Inflammatory oedema was produced in the rat paw by heat (45.5 degrees C), and on the ear by xylene. The oedema was assessed by comparing the ratio of fresh wet weight to dry weight of corresponding injured and non-injured parts.3. Following cellulose sulphate (6.5 mg/kg i.v.), plasma kininogen concentrations were promptly reduced by 90% or more. The reduction in complement titres was statistically significant and ranged from 17 to 65%. No toxic effects were observed. The oedema caused by heat or xylene was not reduced in these rats.4. Cellulose sulphate (80 mg/kg i.p.) given over 3 days depleted plasma kininogen by about 90%, but reduced complement titres only slightly. These rats gained less weight and their condition was poor. Blood clotting was impaired and widespread haemorrhages were found. Heat and xylene produced significantly less oedema than in control rats. This diminished response is attributed to toxic side effects of cellulose sulphate, rather than depleted plasma kininogen and reduced plasma complement.5. The results suggest that the inflammatory reactions to thermal and chemical injury can fully develop when plasma kininogen and complement are lowered.     

Hypertensive drugs and plasma kinins in rats

The influence of phenylephrine (PHE), methoxamine (MET) and ephedrine (EPH) on kininogen and prekallikrein level in plasma was investigated in male Wistar rats. Simultaneously the effect of these drugs on blood pressure was monitored. No changes in kininogenesis were observed during the hypertension period (2 h after ip injection). The significant decrease in kininogen level (by 20-30%) was found 4 h after PHE (5 mg/kg) or EPH (40 mg/kg) and 4-12 h after MET (40 mg/kg) injection. The reduction of kallikrein utilization, indicating an increase in prekallikrein level in plasma, was noted only after PHE (by 34%) or MET (by 44%) administration. Phentolamine (REG) in a dose of 20 mg/kg, which counteracted the hypertensive effect of investigated drugs, abolished the influence of these drugs on kininogen level. The results indicate that the hypertension induced by alpha-adrenoceptor agonists evokes the delayed activation of kininogenesis parallel to the secondary decrease in blood pressure. Such a reaction of kinin system seems to be related to primary alpha-adrenoceptor stimulation, not to the direct influence of hypertensive drugs on kinin system in rat plasma.     

Effect of inhibition of catecholamine synthesis on central catecholamine-containing neurones in the developing albino rat

1. Tyrosine hydroxylase is thought to be the rate limiting enzyme step in catecholamine biosynthesis. Inhibition of this enzyme using alpha-methyl-p-tyrosine resulted in a time dependent depletion (and repletion) of formaldehyde induced fluorescence in catecholamine-containing neurones of the central nervous system in developing and adult rats.2. Dopamine-containing neurones were depleted faster and more completely than noradrenaline-containing neurones.3. The extent of depletion caused by alpha-methyl-p-tyrosine in the initial 6-9 h period was more or less comparable in young and adult rats from the age of 1 week onwards; this suggests that catecholamine turnover increases with age and parallels the increase in catecholamine levels.4. The extent of depletion (and repletion) 18 h after administration of the inhibitor varied in animals of different age.5. Administration of a monoamine oxidase inhibitor just before administration of alpha-methyl-p-tyrosine resulted in a reduction of the extent of depletion caused by the latter drug, indicating that monoamine oxidase is important for the breakdown of catecholamines in rats of all ages.6. It is suggested that the catecholamine-containing neurones of the newborn are biochemically as well as functionally differentiated before completion of morphological differentiation.     

Evidence for the involvement of a plasma kallikrein-kinin system in the immediate hypotension produced by endotoxin in anaesthetized rats.

1. In vitro incubation of normal rat plasma with endotoxin from E. coli (3-10 mg ml-1) in the incubation mixture) caused a dose-dependent increase in levels of free kinin and plasma kallikrein in the presence of o-phenanthroline, together with a mirror-image, dose-dependent decrease in the residual levels of the precursors, plasma prekallikrein and high-molecular-weight kininogen. Low-molecular-weight kininogen levels were not modified. 2. Intravenous injection of endotoxin (3-30 mg kg-1) into the femoral vein of anaesthetized rats resulted in dose-dependent hypotension. In blood collected up to 15 min after injection, the levels of prekallikrein and high-molecular-weight kininogen in plasma were decreased while levels of the active forms, plasma kallikrein and free kinin, showed a transient increase in the blood 1 min after administration of endotoxin. 3. A degradation product of bradykinin, des-Phe8-Arg9-bradykinin, as measured by a newly developed enzyme immunoassay, was detectable up to 5 min after administration of endotoxin. 4. Intravenous infusion of soybean trypsin inhibitor inhibited both the formation of bradykinin and des-Phe8-Arg9-bradykinin and the initial hypotension. 5. It can be concluded from our results that plasma prekallikrein is activated in the blood immediately after administration of endotoxin to rats and that bradykinin is a major cause of the immediate hypotension.     

An improved pharmacological procedure for depletion of noradrenaline: pharmacology and assessment of noradrenaline-associated behaviors

A pharmacological procedure which initially depletes noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) but permits repletion of DA and 5-HT was used to evaluate the role of NA in feeding behavior and intracranial self-stimulation behavior. The rapid-onset 'reserpine-like' vesicular depletion drug RO 4-1284 reduced NA and 5-HT 99% and DA 90% in rat forebrain within 1 h after administration with complete repletion of all amines occurring within 6 to 12 h. Treatment with the dopamine-beta-hydroxylase inhibitor FLA-63 significantly reduced NA (maximum depletion 42%) but not DA or 5-HT over the 12 h period of evaluation. The two drugs together produced a specific depletion of NA. Forebrain levels of NA in subjects pretreated with FLA-63 then given RO 4-1284 0.5 h later were reduced to 2% of control values for 8 h while vesicular stores of DA and 5-HT were repleted 77% and 93%, respectively, within 8 h after administration. Selective depletion of NA, in this manner, reduced deprivation induced food intake and lateral hypothalamic self-stimulation.     

Mechanism of ionophore A23187 induction of plasma protein leakage and of its inhibition by indomethacin

Calcium ionophore A23187 produced a dose-dependent increase in plasma protein leakage on intradermal injection in rats. Studies with mepyramine and cyproheptadine indicated that histamine and 5-hydroxytryptamine (5-HT) partially contribute to the ionophore action and experiments with compound 48/80 supported these findings. Depletion of plasma kininogen levels with cellulose sulphate administered indomethacin inhibited the ionophore response in a dose-dependent manner. The inhibition was not reversed by intradermally injected prostaglandin E2 (PGE2) in doses up to 50 ng/site, suggesting that PGE2 also may not be an important mediator. It is proposed that the ionophore produces plasma protein leakage by an indirect (through histamine and 5-HT release) and a direct action on vascular endothelial cells and that indomethacin antagonises both actions by inhibiting calcium transport processes.     

Disposition and metabolism of [14C]sparfloxacin in the rat.

Disposition and metabolism of [carbonyl-14C]sparfloxacin SPFX, 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, AT-4140; CAS 110871-86-8), a novel antimicrobial quinolone, were studied in rats mainly after oral administration at 10 mg/kg. SPFX was absorbed from the whole area of small intestine as shown by the loop method. The extent of absorption was around 70% when estimated by AUC, urinary excretion and biliary excretion. Plasma level of radioactivity reached Cmax of 1.32 micrograms eq/ml within 1 h after oral administration and decreased with a half-life of about 4 h. Higher levels of radioactivity than that in plasma were seen in kidney, liver, submaxillary gland, lung, trachea and many other tissues and lower levels, in eye ball, brain and some others. Most tissue levels decreased with time essentially in parallel with plasma level. In pregnant rats, levels of fetal radioactivity amounted to about 60% of maternal plasma level. In lactating rats, milk was found to contain radioactivity several times as high as plasma level, which decreased with a similar half-life. SPFX was bound to plasma protein, mainly to albumin, at about 40%. Unchanged SPFX and its glucuronide were found in the plasma, milk, bile and urine. Within 48 h, about half of the dosed radioactivity was excreted in the bile, and part of which was re-absorbed. Within 96 h, about 20 and 80% of dose were found in the urine and feces, respectively.     

Croconazole metabolism in rats

1. Following subcutaneous administration of 1-(2-(3-chlorobenzyloxy)phenyl)vinyl)-1H-imidazole (croconazole) to rats, four metabolites were identified by comparison of their mass and n.m.r. spectra, g.l.c., and t.l.c. with those of synthetic compounds and enzyme hydrolysis. These compounds are o-hydroxyacetophenone sulphate (M1S), 1-(1-(2-hydroxyphenacyl)vinyl)-1H-imidazole sulphate (M12S), 2-(3-chlorobenzyloxy)phenacyl alcohol (M2), and 2-(3-chlorobenzyloxy)benzoic acid (M9-1). 2. At 10 mg/kg dosing of croconazole the elimination rate of the unchanged drug from plasma was faster in male than in female rats. 3. The percentage of excretion of M12S in 24 h urine was 17% for males and 7.5% for females, and that of M1S was 6.6% for males and 6.5% for females. The percentage of excretion of M2 in 24 h bile was 14% for males and 22% for females, and that of M9-1 was 3.7% for males and 1.6% for females.     

Croconazole metabolism in rats

1. Following subcutaneous administration of 1-(2-(3-chlorobenzyloxy)phenyl)vinyl)-1 H-imidazole (croconazole) to rats, four metabolites were identified by comparison of their mass and n.m.r. spectra, g.l.c., and t.l.c. with those of synthetic compounds and enzyme hydrolysis. These compounds are o-hydroxyacetophenone sulphate (M1S), 1-(1-(2-hydroxyphenacyl)vinyl)-1H-imidazole sulphate (M12S), 2-(3-chlorobenzyloxy)phenacyl alcohol (M2), and 2-(3-chlorobenzyloxy)benzoic acid (M9-1).

2. At 10?mg/kg dosing of croconazole the elimination rate of the unchanged drug from plasma was faster in male than in female rats.

3. The percentage of excretion of M12S in 24?h urine was 17% for males and 7.5% for females, and that of M1S was 6.6% for males and 6.5% for females. The percentage of excretion of M2 in 24?h bile was 14% for males and 22% for females, and that of M9-1 was 3.7% for males and 1.6% for females.     

Metabolic fate of the new cardiotonic denopamine in animals. 3rd communication: placental transfer and excretion into milk in the rat

3H-labelled (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol (denopamine, TA-064) was administered orally to pregnant rats at a dose of 5 or 60 mg/kg on the 14th or 20th day of pregnancy. Irrespective of the doses and the stages of pregnancy, radioactivity in the fetus reached a peak at 30 min after administration, being 1/7 to 1/25 of the maternal plasma levels. Total radioactivity in each fetus at 30 min was estimated to be only about 0.002 to 0.06% of the dose. Disappearance of radioactivity from the fetus, uterus and amniotic fluid was slightly slower than that from the maternal plasma. After 3H-denopamine (5 mg/kg) was orally administered to lactating rats on the 12th day after delivery, radioactivity in milk was generally lower than in the blood of the dams, and time to the peak levels in milk tended to delay as compared with that in the blood. The levels of radioactivity in the blood of the sucklings, nursed by their dams, at 1 h after nursing were about 1/30 of the maternal blood levels, showing a slight transfer of the drug and/or its metabolites via milk. At 24 h after administration, radioactivity levels in the sucklings decreased to near the detection limit. The results of whole body autoradiography were generally consistent with the quantitative data on the placental transfer and excretion into milk.     

Increased oral clearance of metoprolol in pregnancy

The disposition of oral metoprolol was studied in 5 women during the last trimester of pregnancy and 3 to 5 months after delivery. After a single oral dose of 100 mg the individual peak plasma concentration in the pregnant state was only 20-40% of that after pregnancy. The plasma half-lives of metoprolol were about the same during (average 1.3 h) and after pregnancy (average 1.7 h). By contrast, the area under the plasma concentration versus time curve was much smaller during (mean 262 nmol/1 X h) than after (mean 1298 nmol/1 X h) pregnancy, resulting in an average apparent oral clearance (Clo) of metoprolol that was 4.4 times higher during (362 ml X kg-1 body-weight X min-1) than after pregnancy. The increased Clo in pregnancy is assumed to be due to enhanced hepatic metabolism of the drug. The possible clinical consequence of the difference in the disposition of metoprolol is discussed.     

Pharmacokinetics and fate of 3H-trospectomycin sulphate, a novel aminocyclitol antibiotic, in male and female rats.

1. The pharmacokinetics and fate of 3H-trospectomycin sulphate, a novel aminocyclitol antibiotic, were examined in male and female rats after intramuscular (i.m.), intravenous (i.v.) and subcutaneous (s.c.) dosing. 2. Total radioactivity levels in plasma were associated with unchanged trospectomycin. Two radioactive components were found in urine, one was indistinguishable from trospectomycin and the other was probably a degradation product formed after excretion or during storage rather than a metabolite. 3. The disappearance of drug from plasma followed a biphasic pattern with half lives of 0.3-0.4 h and 45-80 h and a large distribution volume, which indicated some retention of drug by tissues. Clearance rates were within the normal range for glomerular filtration rate, which indicated that the primary process of elimination is filtration of unchanged drug. 4. Excretion was initially rapid (greater than 40% by 4 h) and mainly into urine (faecal excretion greater than 20%). Urinary excretion was significantly larger in males than females but faecal excretion was significantly smaller, so that there was no significant difference in total excretion. 5. The bioavailability following s.c. dosing was only approximately 75% but there were few other biologically significant differences between the routes of administration. Absorption following i.m. and s.c. dosing was rapid. 6. Clearance rate and volume of distribution were higher in males than females. Over the dose range 50-200 mg/kg the pharmacokinetics appeared to be mostly linear.     

Oral absorption, metabolism and excretion of 1-phenoxy-2-propanol in rats

1. This study was designed to determine the absorption, metabolism and excretion of 1-phenoxy-2-propanol in Fischer 344 rats following oral administration in an effort to bridge data with other propylene glycol ethers. 2. Rats were administered a single oral dose of 10 or 100 mg kg(-1) 14C-1-phenoxy-2-propanol as a suspension in 0.5% methyl cellulose ether in water (w/w). Urine was collected at 0-12, 12-24 and 24-48 h and faeces at 0-24 and 24-48 h post-dosing and the radioactivity was determined. Urine samples were pooled by time point and dose level and analysed for metabolites using LC/ESI/MS and LC/ESI/MS/MS. 3. The administered doses were rapidly absorbed from the gastrointestinal tract and excreted. The major route of excretion was via the urine, accounting for 93 +/- 5% of the low and 96 +/- 3% of the high dose. Most of the urinary excretion of radioactivity occurred within 12 h after dosing; 85 +/- 2% of the low and 90 +/- 1% of the high dose. Total faecal excretion remained < 10%. Rats eliminated the entire administered dose within 48 h after dosing; recovery of the administered dose ranged from 100 to 106%. Metabolites tentatively identified in urine were conjugates of phenol (sulphate, glutathione) with very low levels (< 2%) of hydroquinone (glucuronide), conjugates of parent compound (glucuronide, sulphate) and a ring-hydroxylated metabolite of parent. There was no free parent compound or phenol in non-acid-hydrolysed urine. In acid-hydrolysed urine, 61% of the dose was identified as phenol and 13% as 1-phenoxy-2-propanol. Although the parent compound was stable to acid hydrolysis, some of the phenol in acid hydrolysed urine may have arisen from degradation of acid-labile metabolite(s) as well as hydrolysis of phenol conjugates. 4. Rapid oral absorption, metabolism and urinary excretion of 1-phenoxy-2-propanol in rats were similar to other propylene glycol ethers.     

Kinetics of 3-(4-methylbenzylidene)camphor in rats and humans after dermal application

The toxicokinetics of 4-MBC after dermal administration were investigated in human subjects and in rats. Humans (3 male and 3 female subjects) were exposed to 4-MBC by topical application of a commercial sunscreen formulation containing 4% 4-MBC (w/w), covering 90% of the body surface and resulting in a mean dermal 4-MBC dose of 22 mg/kg bw. In rats, dermal 4-MBC doses of 400 and 2000 mg/kg bw were applied in a formulation using an occlusive patch for 24 h. Concentrations of 4-MBC and its metabolites were monitored over 96 h in plasma (rats and humans) and urine (humans). In human subjects, plasma levels of 4-MBC peaked at 200 pmol/ml in males and 100 pmol/ml in females 6 h after application and then decreased to reach the limit of detection after 24 h (females), respectively, 36 h (males). After dermal application of 4-MBC, peak plasma concentrations of 3-(4-carboxybenzylidene)-6-hydroxycamphor were 50-80 pmol/ml at 12 h and of 3-(4-carboxybenzylidene)camphor were 100-200 pmol/ml at 24 h. In male and female rats, peak plasma levels of 4-MBC were 200 (dose of 400 mg/kg bw) and 1 200 pmol/ml (dose of 2000 mg/kg bw). These levels remained constant for up to 24-48 h after dermal application. Peak plasma concentrations of 3-(4-carboxybenzylidene)-6-hydroxycamphor were 18,000 pmol/ml (males) and of 3-(4-carboxybenzylidene)camphor were 55,000 pmol/ml (females) between 48 and 72 h after application of the high dose of 4-MBC. In human subjects, only a small percentage of the dermally applied dose of 4-MBC was recovered in the form of metabolites in urine, partly as glucuronides. The obtained results suggest a more intensive biotransformation of 4-MBC in rats as compared to humans after dermal application and a poor absorption of 4-MBC through human skin.     

Asymmetric Membrane Osmotic Capsules for Terbutaline Sulphate

The aim of the present study was to design an asymmetric membrane capsule, an osmotic pump-based drug delivery system of ethyl cellulose for controlled release of terbutaline sulphate. asymmetric membrane capsules contains pore-forming water soluble additive, sorbitol in different concentrations in the capsule shell membrane, which after coming in contact with water, dissolves, resulting in an in situ formation of a microporous structure. The terbutaline sulphate is a β-adrenoreceptor agonist widely used in the treatment of asthma. The oral dosage regimen of terbutaline sulphate is 5 mg twice or thrice daily, the plasma half-life is approximate 3-4 h and it produces GI irritation with extensive first pass metabolism. Hence, terbutaline sulphate was chosen as a model drug with an aim to develop controlled release system. Different formulations of ethyl cellulose were prepared by phase inversion technique using different concentrations of sorbitol as pore forming agent. It was found that the thickness of the prepared asymmetric membrane capsules was increased with increase in concentration of ethyl cellulose and pore forming agent, i.e. sorbitol. The dye release study in water and 10% sodium chloride solution indicates that, the asymmetric membrane capsules follow osmotic principle to release content. The pores formed due to sorbitol were confirmed by microscopic observation of transverse section of capsule membrane. Data of in vitro release study of terbutaline sulphate from asymmetric membrane capsules indicated that, the capsules prepared with 10% and 12.5% of ethyl cellulose and 25% of sorbitol released as much as 97.44% and 76.27% in 12 h, respectively with zero order release rate. Hence asymmetric membrane capsule of 10% ethyl cellulose and 25% of sorbitol is considered as optimum for controlled oral delivery of terbutaline sulphate.     

Kininogen and prekallikrein increases in the blood of streptozotocin-diabetic rats are normalized by insulin in vivo and in vitro

Twelve days following treatment with 50 mg/kg streptozotocin (STZ), male rats were diabetic, with a three-fold increase in blood glucose (P<0.001) and increased plasma bradykinin (BK) kininogen reserves of [high-(HK)- and low- (LK)-molecular-weight kininogens,+162%, P<0.01 and +63%, P=0.05, respectively], as determined by bioassay of BK released by trypsin from these precursors under standardized conditions. Administration of a single dose (10 U/kg i.v.) of regular insulin decreased plasma HK and LK to near non-diabetic values. Within 24 h these values had returned to levels characteristic of uncorrected diabetes. Prekallikrein (PK), the precursor of plasma kallikrein, an enzyme which releases BK from HK, was increased by 63.4% (P<0.05) in STZ-diabetes, but dropped to near normal levels following insulin treatment. Incubation of whole blood of normal or diabetic rats with 0.02-0.2 mU/ml regular insulin for 10 min at 37 C, decreased HK (P<0.01) and PK (P<0.05) and led to the appearance (P<0.05) of Arg-Pro-Pro-Gly-Phe, a partially stable product of BK metabolism, detected in the incubation media by an enzyme-linked immunosorbent assay (ELISA). Incubation of cell-free plasma insulin had no effect on these parameters, suggesting that blood cells, possibly neutrophils, are required by insulin for the activation of plasma PK to kallikrein leading to BK release. Insulin may be a factor modulating BK formation; its reduction in diabetes may explain increases of plasma kininogen and PK observed in this condition.     

Species and tissue differences in the toxicity of 3-butene-1,2-diol in male Sprague-Dawley rats and B6C3F1 mice.

3-Butene-1,2-diol (BDD) is a major metabolite of 1,3-butadiene (BD), but the role of BDD in BD toxicity and carcinogenicity remains unclear. In this study, the acute toxicity of BDD was investigated in male Sprague-Dawley rats and B6C3F1 mice. Of the rats given 250 mg/kg BDD, 2 out of 4 died within 24 h; rats experienced hypoglycemia, significant alterations of liver integrity tests, and had lesions in the liver 4 h after treatment, but no lesions were detected in extrahepatic tissues. Rat hepatic GSH and GSSG levels were significantly depleted at both 1 and 4 h after the BDD treatment. Rats administered 200 mg/kg BDD also had liver lesions but no death or hypoglycemia was observed four or 24 h after treatment; these rats had depleted hepatic GSH and GSSG levels at 1 h but not at 4 or 24 h after treatment. Mice administered 250 mg/kg BDD exhibited modest alterations of liver integrity tests, but no death, hypoglycemia, or lesions in any tissue, and hepatic GSH and GSSG levels were depleted at 1 h but not at 4 h. The plasma half-life of BDD was four times longer in rats than in mice. Additional studies in rats showed the depletion of hepatic GSH and GSSG preceded the BDD-induced hypoglycemia and hepatotoxicity. Thus, the long half-life of BDD in rat plasma and the sustained depletion of hepatic GSH and GSSG may in part explain the higher sensitivity of the rat to BDD-induced hepatotoxicity. Furthermore, the results indicate that BDD may play a role in BD-induced toxicity.