Subchronic hepatotoxicity evaluation of bromobenzene in Fischer 344 rats

Male Fischer 344 (F344) rats were exposed to bromobenzene (BB) for 5 days and 2, 4 and 13 weeks. BB was administered by gavage (corn oil vehicle) at doses of 0, 25, 100, 200, 300 and 400 mg kg^?1 per day. Endpoints evaluated included clinical observations, body weights, liver weights, serum chemistry, blood BB, gross pathology and liver histopathology. There were no BB exposure‐related clinical signs of toxicity. Mean body weight decreased by 5–10% compared with control in the 400 mg kg^?1 per day group. Liver weight increases were dose‐ and exposure time‐related and statistically significant at ≥25 mg kg^?1 per day. Incidence and severity of centrilobular cytoplasmic alteration and hepatocyte hypertrophy were related to dose and exposure time. At early time points (5 days and 2 weeks), centrilobular inflammation, including granulomatous areas, and necrotic and anisokaryocytic hepatocytes were observed in rats of the two highest BB dose groups. Blood BB concentrations increased linearly with dose and at 13 weeks ranged from 8 to 136 µg ml^?1 (25–400 mg kg^?1 per day). In conclusion, rats administered BB doses up to 400 mg kg^?1 per day for up to 13 weeks had mild liver effects. A NOAEL of 200 mg kg^?1 per day was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ≥ 400 mg kg^?1 per day. Copyright © 2012 John Wiley & Sons, Ltd.     

Ninety days of repeated gavage administration of Rhodiola imbricata extract in rats

Rhodiola imbricata is a high‐altitude plant, possesses adaptogenic, immunomodulatory, anti‐oxidant and cytoprotective activity, and is widely used in traditional medicine. The present study was designed to ascertain the safety of aqueous extract of R. imbricata root when administered by gavage to rats for 90 days. Four groups of animals, each consisting of 15 males and 15 females, were administered 0, 100, 250 or 500 mg kg^?1 extract, in a single dose per day. The experimental rats when administered 100 mg kg^?1 of extract did not show any significant change in their body weight gain, organ/body weight ratio, or histological, hematological and biochemical variables studied. However, at higher doses of 250 and 500 mg kg^?1 extract, an increase in the body weight of rats of both the sexes was apparent without any change in their organ/body weight ratio. Furthermore, a noteworthy increase in plasma glucose and protein levels was recorded at both the higher doses, which were restored to normal after a 2‐week withdrawal of treatment. Based on the findings of this study, the no observed effect level was 100 mg kg^?1 body weight per day of aqueous root extract of R. imbricata in rats administered subchronically. Copyright © 2011 John Wiley & Sons, Ltd.     

Developmental toxic potential of di‐n‐propyl phthalate administered orally to rats

The objective of this study was to evaluate the developmental toxic potential of di‐n‐propyl phthalate (DnPP) in rats. Pregnant Sprague–Dawley rats were given DnPP at doses of 0 (olive oil), 0.5, 1 and 1.5 g kg^?1 per day, by gavage, on gestation days 6–20. Benchmark doses were calculated for the effects of DnPP on fetal weight and anogenital distance of the male fetuses. Maternal body weight gain was significantly reduced at 1.5 g kg^?1 per day, over gestation days 6–9. DnPP‐treated dams also showed a statistically significant increase in liver weight and a mild but statistically significant peroxisomal enzyme induction at 1 or 1.5 g kg^?1 per day. Male and female fetal body weights were significantly reduced at 1.5 g kg^?1 per day. There was a statistically significant decrease in the anogenital distance of the male fetuses at 1 and 1.5 g kg^?1 per day, and three males (of 75) showed malpositioned testis at the high dose. The mean percentage of fetuses per litter with cervical and thoracic rudimentary ribs was significantly increased at 1 and 1.5 g kg^?1 per day. Delayed ossification was seen at 1 g kg^?1 per day (phalanges) and 1.5 g kg^?1 per day (hyoid, sternebrae, and phalanges). No treatment‐related effects on prenatal viability or on fetal external or visceral malformations or variations were observed at any dose. Thus, there was no evidence of teratogenicity up to the high dose of 1.5 g kg^?1 per day. The no‐observed‐adverse‐effect level (NOAEL) for developmental toxicity was 0.5 g kg^?1 per day. Copyright © 2010 JohnWiley & Sons, Ltd.     

The effects of chronic treatment with d-amphetamine on food intake,body weight,locomotor activity and subcellular distribution of the drug in rat brain

Female Wistar rats were treated chronically with d-amphetamine sulphate in drinking water. The concentrations of amphetamine were 0.01%, 0.02%, 0.03%, 0.04% and 0.05% in the 1st, 2nd, 3rd, 4th, and 5th week of treatment. The consumed doses of amphetamine increased from 16 mg/kg on the first day up to 90 mg/kg on the 36th day of treatment. The effects of chronic treatment with amphetamine on food intake, body weight and locomotor activity of rats were determined. The rats developed tolerance to the overall toxicity and to the anorexigenic effect of maphetamine. No tolerance to the effects of the drug on body weight and locomotor activity was observed. The concentration of H³-d-amphetamine in brains of chronically treated rats is significantly higher than in controls. No difference in the pattern of distribution of radioactivity among the subcellular fractions of rat brain was observed between control and chronically treated groups. The relationship between developmen tof tolerance and the concentration of amphetamine in the brain is discussed.     

Oral Toxicity Study of 2-Pentenenitrile in Rats with Reproductive Toxicity Screening Test

A combined repeated-dose toxicity study with reproduction was conducted with 2‐pentenenitrile (2-PN). Rats (10/sex per dose level) were dosed with 2-PN once daily by gavage at dose levels of either 0, 1, 3, or 10 mg kg^?1 day^?1 for 28 days, prior to and during cohabitation, and through day 3 of lactation. General clinical observations were recorded daily; body weights were recorded weekly. A neurobehavioral evaluation consisting of a functional observational battery and motor activity was conducted in all parental rats (10/sex per group). Clinical pathology parameters (hematology, clinical chemistry, coagulation) were measured in parental rats. Pup weights and clinical signs were recorded at birth and on lactation day 4. Parental rats were given a gross pathological examination, organ weights were obtained, and histological examination was conducted for the control and 10 mg kg^?1 day^?1 groups. No effects were seen with regard to mortality, clinical signs, functional observational battery and motor activity, hematology, or organ weights. Females receiving 10 mg/kg and males from all dose groups showed lower body weight gains and feed efficiency. Increased albumin concentrations were seen in both sexes given 10 mg/kg. Females in the 10 mg/kg group showed degeneration of the olfactory mucosa. No effects on the numbers of pups born, number surviving to lactation day 4, pup weight, and no gross anatomical development changes were observed. Under the conditions of this study, the no-observed-effect level (NOEL) for systemic toxicity in rats was 3 mg kg^?1 day^?1, based on degeneration of olfactory mucosa in females at 10 mg kg^?1 day^?1. The NOEL for reproductive and neurobehavioral toxicity in rats and for toxicity to offspring was 10 mg kg^?1 day^?1, the highest dose level tested.     

Effects of Jatropha oil on rats following 28‐day oral treatment

Jatropha oil is an emerging feedstock for the production of biodiesels. The increasing use of this nonedible, toxic oil will result in higher potential for accidental exposures. A repeated‐dose 28‐day oral toxicity study was conducted to provide data for risk assessment. Jatropha oil diluted in corn oil was administered by gavage to male and female rats at 0.5, 5, 50 and 500 mg kg^?1 body weight per day for 28 consecutive days. Control rats were administered corn oil only. The growth rates and consumption of food and water were monitored. At necropsy, organs were weighed and hematological parameters assessed. Serum clinical chemistry and C‐reactive protein were measured and histological examinations of organs and tissues were performed. Markedly depressed growth rate was observed in males and females receiving Jatropha oil at 500 mg kg^?1 per day. Decreased white blood cell and lymphocyte counts were detected in females at 50 and 500 mg kg^?1 per day and in males at 500 mg kg^?1 per day. These changes were correlated to mild and reversible histological changes in male and female spleens. In the liver, a mild increase in portal hepatocytes cytoplasm density was observed in males and females, while periportal vacuolation was observed exclusively in females. Mild acinar proliferation was observed in the female mammary glands at all dose levels. It is concluded that Jatropha oil produces adverse effects on female rats starting at 50 mg kg^?1 per day with decreased white blood cell and lymphocyte counts and at 500 mg kg^?1 per day in both genders in term of depressed growth rates. Copyright © 2011 John Wiley & Sons, Ltd.     

Effects of Thyrotrophin-releasing Hormone Tartrate and its Sustained Release Formulation on Cerebral Glucose Metabolism in Aged Rats

The effects of a sustained release formulation of thyrotrophin-releasing hormone (TRH) over two weeks (TRH-SR, 10 or 50 mg kg^? equivalent to 0.56 or 2.80 mg kg^? free TRH, respectively) and repeated treatment with TRH tartrate (TRH-T, 0.3, 1.0 or 3.0 mg kg^?, equivalent to 0.2, 0.7 or 2.0 mg kg^? free TRH, respectively) on the rate of local cerebral glucose utilization (LCGU) were investigated using the quantitative autoradiographic 2-deoxy-[¹⁴C]d -glucose method in various brain regions of aged rats. In aged rats (28 months old), the LCGU was significantly reduced as compared with young adult rats (3 months old), while treatment with TRH-SR ameliorated the reduction of the LCGU in a dose-dependent manner. The brain regions ameliorated by TRH-SR were the auditory cortex, septal nucleus, substantia nigra, cerebellar cortex and cerebellar nucleus. In contrast, once-daily repeated treatment over one week with TRH-T at a dose of 0.3 mg kg^? (equivalent to 50 mg kg^? of TRH-SR) had no effect on the reduced LCGU in various brain regions in aged rats (27 months old), whereas treatment with a higher dose of TRH-T (0.7 or 2.0 mg kg^? free TRH) significantly ameliorated the reduction. The comparison of the ameliorating potencies between TRH-T and TRH-SR indicated that TRH-SR had a potency about 7 times greater than TRH-T.     

Evidence for a difference in mechanism of action between fenfluramine- and amphetamine-induced anorexia

The influence of drugs, active on 5-hydroxytryptamine (5-HT) mechanisms, has been examined on the anorexigenic activity of fenfluramine and (+)-amphetamine in rats trained to consume their daily food ration during 6 h. Chlorimipramine, which inhibits the re-uptake mechanisms in central 5-HT neurons, and the 5-HT blocking drugs methergoline and methysergide were used. Fenfluramine, 7.5 mg kg^?1, and amphetamine, 2.5 mg kg^?1, given 1/2 h before feeding reduced the food intake during the following 2 h to approximately 40% compared with control days. Pretreatment with methergoline in the optimal dose (1 mg kg^?1) produced only a weak but significant antagonism to amphetamine anorexia, whereas the fenfluramine anorexia was strongly antagonized by methergoline in all doses tested (0.3, 1 and 3 mg kg^?1). Methysergide (0.1, 0.3, 1 and 3 mg kg^?1) showed no significant antagonism against amphetamine or fenfluramine anorexia. Chlorimipramine produced a strong antagonistic effect to the fenfluramine anorexia, but showed no antagonism against amphetamine. In contrast the highest dose of chlorimipramine (20 mg kg^?1) potentiated amphetamine anorexia. The present results together with other evidence discussed support the conclusion that 5-HT mechanisms are involved in fenfluramine anorexia, whereas amphetamine anorexia seems mainly correlated with catecholamine dependent mechanisms.     

Drug-induced alterations in the activity of rat brain cholinergic enzymes. I. In vitro and in vivo effect of amphetamine

The effect of acute and chronic administration of d-amphetamine sulphate on rat brain acetylcholinesterase and choline acetylase activities has been studied. High concentrations (10⁻² M) of amphetamine were found to activate both AChE and ChAc activities in crude extracts from rat brain. Daily amphetamine injections into rats produced after some time an increase in ChAc activity of the brain but had no significant effect on its AChE activity. There was a marked inhibition in eating behaviour (95%) following the first day of treatment. Eating behaviour increased to about 40% of the control level after 14 days of treatment. There was a gradual reduction in body weight. The progressive changes in drug-induced eating behaviour and body weight showed some correlation to changes in ChAc activity. The possibility of amphetamine-induced adrenergic activity interacting with cholinergic function iis discussed.     

Induction of oxidative stress in liver and kidney of rats exposed to Nigerian bonny light crude oil

The local population of Niger‐Delta in the Southern part of Nigeria have used bonny light crude oil (BLCO) as a remedy for various ailments and are exposed to some extent to this widespread environmental contaminant or its metabolites through the food chain. BLCO's hepatorenal toxicity was studied using oxidative stress indices to elucidate the precise nature and mechanism of action. BLCO was orally administered at concentrations of 0, 200, 400, and 800 mg kg^?1 to adult male rats for 7 days. After exposure, kidney weight was unaffected, but liver weight decreased significantly at 800 mg kg^?1 only compared with control. BLCO exposure resulted in dose‐dependent elevation of serum aminotransferases, total bilirubin, urea, and creatinine. Activities of superoxide dismutase and catalase decreased significantly, whereas γ‐glutamyltransferase activity and the level of glutathione increased significantly in BLCO‐treated animals compared with control in both liver and kidney of rat. Renal activities of glucose‐6‐phosphatase and 5′‐nucleotidase markedly decreased in a dose‐dependent manner in BLCO‐exposed rats. In addition, the levels of hydrogen peroxide and lipid peroxidation significantly increased, dose dependently, in liver and kidney of BLCO‐treated rats compared with control. BLCO‐treated rats showed marked degeneration of kidney evident in cortical hemorrhages, tubular necrosis, protein casts, and cellular infiltration. However, no treatment‐related liver histopathology was observed. The results suggested that BLCO elicits disruption of antioxidant status and concomitant elevation of hydrogen peroxide and lipid peroxidation differentially in liver and kidney of rats. The hepatorenal toxicity of BLCO could be due to induction of oxidative stress in liver and kidney. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

Effect of a mercurial ayurvedic drug (kajyoli) on the ion concentration and respiratory activity in brain,liver and kidney of the albino rat

The effect of a mercurial ayurvedic drug (kajyoli), on the concentration of Na⁺, K⁺ and Ca²⁺ in rat liver, kidney and brain, and on the respiratory activity of these tissues is reported. The doses used were 20 mg and 40 mg. day^?1. kg^?1 body wt. daily for 30 days, the lower level being equivalent to the human dose. A marked dose-dependent decrease in respiratory activity occurred in the three tissues. The only significant changes seen in the ion concentration were a decrease in Na⁺ at the higher dose level in the kidney and a dose-dependent decrease in Ca²⁺in the liver.     

Effects of melamine on pregnant dams and embryo‐fetal development in rats

There are worldwide concerns regarding the potential adverse effect of melamine. This study investigated the potential effects of melamine on pregnant dams and embryo‐fetal development in Sprague–Dawley rats following maternal exposure on gestational days (GD) 6–20. Melamine was administered to pregnant rats by gavage at doses of 0, 200, 400 and 800 mg kg^?1 per day (n = 8–10 for each group). All dams were subjected to a Caesarean section on GD 21 and their fetuses were examined for morphological abnormalities. With administration of melamine at 800 mg kg^?1 per day, maternal toxicity manifested as increased incidences of clinical signs and death, lower body weight gain and food intake, and increases in heart, adrenal gland and kidney weights. Histopathological examinations revealed an increase in incidences of congestion, tubular necrosis/degeneration, crystals, casts, inflammatory cells in tubules, tubular dilation and tubular hyaline droplets in the maternal kidneys, while fetal kidneys (one fetus/litter) did not show any histopathological changes. Developmental toxic effects included a decrease in fetal weight, an increase in the incidence of skeletal variations and a delay in fetal ossification. No treatment‐related maternal or developmental effects were observed at doses ≤400 mg kg^?1 per day. These results show that 15‐day repeated oral dosing of melamine is embryo‐/fetotoxic at a maternotoxic dose, but not teratogenic in rats. The no‐observed‐adverse‐effect level of melamine for pregnant dams and embryo‐fetal development is considered to be 400 mg kg^?1 per day. Copyright © 2011 John Wiley & Sons, Ltd.     

The Effect of Indobufen on the Activities of Selected Rat Liver Phase I and Phase II Drug Metabolizing Enzymes,Peroxisomal β-oxidation and Hepatic Glutathione Status

Abstract— Oral administration of indobufen to male rats for three days at daily doses of 5, 10 and 20 mg kg^?1 resulted in no changes in liver total glutathione, cytosolic glutathione S-transferases or microsomal epoxide hydrolase. Reduced glutathione appeared slightly diminished to about 84% of control at the highest dose level. Microsomal cytochrome P450-dependent ethoxyresorufin O-de-ethylase and pentoxyresorufin de-alkylase activities were decreased to 64% (not significantly) and 67% of control at the lowest dose level. 6α- and 7α-Hydroxytestosterone activities were decreased to 67 and 68% of control at the highest dose level. Cyanide-insensitive peroxisomal fatty acid β-oxidation was increased to 223, 261 and 232% of control at doses of 5, 10, and 20 mg kg^?1, respectively. The results obtained in this study are indicative of the action of indobufen as a weak peroxisome proliferator in male rat liver, and suggest a slight but toxicologically insignificant inhibitory action of this drug on microsomal cytochrome P450-dependent enzyme activities.     

Accelerated metabolism of probenecid during long-term treatment of rats with anticonvulsant drugs: effect on central serotonin turnover studies

Studies were carried out in rats to determine the effects of long-term administration (once daily for 9 days) of phenytoin (50 mg kg^?1), sodium phenobarbital (25 mg kg^?1), primidone (50 mg kg^?1), and l-5-hydroxytryptophan (l-5-HTP; 50 mg kg^?1) on probenecid metabolism and on serotonin turnover rates as estimated by probenecid-induced accumulation of 5-hydroxyindoleacetic acid (5-HIAA) in brain. Without probenecid, mean brain 5-HIAA levels were similar in control and drugtreated rats, suggesting that the turnover rate of brain serotonin was not affected by the chronic anticonvulsant drug pretreatment. But, in the rats treated with phenobarbital, the rate of accumulation of 5-HIAA in brain during the first 90 min after probenecid (200 mg kg^?1) was significantly lower than the rate of accumulation in the control rats. Also, at 6 hr after probenecid, brain 5-HIAA levels were similar to pre-probenecid values in the rats pretreated with phenobarbital or primidone, while 5-HIAA levels were still increased in the rats treated with phenytoin, l-5-HTP, or vehicle. Examination of serum revealed that the concentration of probenecid in serum decreased more rapidly in rats pretreated with either primidone or phenobarbital than in rats given vehicle, l-5-HTP, or phenytoin. It is likely, therefore, that the decreased 5-HIAA accumulation in the brains from these animals were due to decreased inhibition of 5-HIAA efflux and not to a decreased rate of serotonin turnover in brain. Since a sustained inhibition of acid transport by probenecid is required, drug interactions with probenecid may be important in clinical studies using probenecid-induced accumulations of 5-HIAA in cerebrospinal fluid to estimate central serotonin turnover rates.     

Long-term feeding effects of stevioside sweetener on some toxicological parameters of growing male rats

Several attempts to decrease sugar demand by introducing stevioside as a sugar substitute in children's food products have been made, but safety issues were concerned. This exploratory study investigated the effects of stevioside low dose (SL), high dose (SH) and low dose with inulin (SL + I) for 12 weeks on the body weight, organ relative weight, hematological and biochemical parameters and enzyme activities of young male rats. The SL dose used in this study was 15 mg kg^?1 per day and the SH dose was 100‐fold the low dose. Enormous similarities in most parameters were observed with no significant differences between SL, SL + I and control except in the lipid profile. Total lipid reduction in SL and SL + I and significant high‐density lipoprotein increase in SL + I were observed, which may be considered as clinically beneficial. Significant decreases in serum tartrate‐resistant acid phosphatase activity were also observed in all treatments. Treatment with SH caused significant changes in all investigated toxicological parameters. The results indicated that, although the SL dose was higher than the stevioside temporary accepted daily intake (5.0 mg kg^?1 body weight), no toxicological effects were observed in SL or SL + I on body weight, organ relative weight, hematological and biochemical parameters or enzyme activities investigated in this study, whereas stevioside high dose (1500 mg kg^?1 per day) may be considered as a toxic dose for the same biological parameters in young male rats. However, the effects of SL, SH and SL + I on serum tartrate‐resistant acid phosphatase activity need more investigation. Copyright © 2010 John Wiley & Sons, Ltd.     

Validation of the intact rat weanling uterotrophic assay with notes on the formulation and analysis of the positive control chemical in vehicle

The intact female weanling version in the Organization for Economic Cooperation and Development (OECD) uterotrophic assay Test Guideline (TG) 440 is proposed as an alternative to the adult ovariectomized female version, because it does not involve surgical intervention (vs the ovariectomized version) and detects direct/indirect‐acting estrogenic/anti‐estrogenic substances (vs the ovariectomized version which detects only direct‐acting estrogenic/anti‐estrogenic substances binding to the estrogen receptor). This validation study followed OECD TG 440, with six female weanling rats (postnatal day 21) per dose group and six treatment groups. Females were weighed and dosed once daily by oral gavage for three consecutive days, with one of six doses of 17α‐ethinyl estradiol in corn oil at 5 ml kg^?1 at 0 and 0.1–10 µg kg^?1 per day. On postnatal day 24, the juvenile females were euthanized by CO₂ asphyxiation, weighed, livers weighed and uteri weighed wet and blotted. The presence or absence of vaginal patency was recorded. Absolute and relative (to terminal body weight) uterine wet and blotted weights and uterine luminal fluid weights were significantly increased at 3.0 and 10.0 (both P < 0.01) µg kg^?1 per day, and increased to ～140% of control values at 1.0 µg kg^?1 per day (not statistically significantly). In vivo body weights, weight changes, feed consumption, liver weights and terminal body weights were unaffected. Vaginal patency was not acquired in any female at any dose, although vaginal puckering was observed in one female at 10.0 µg kg^?1 per day. Therefore, this intact weanling uterotrophic assay is validated in our laboratory for use under US and European endocrine toxicity testing programs/legislation. Copyright © 2010 John Wiley & Sons, Ltd.     

Distribution of Bismuth in the Rat after Oral Dosing with Ranitidine Bismuth Citrate and Bismuth Subcitrate

Bismuth preparations are used world-wide for the management of peptic ulcer disease, for eradication of Helicobacter pylori, and in the prevention and treatment of diarrhoea. However neurological toxicity of bismuth has always been a major concern and evidence has been found of the absorption of bismuth. Recent studies have suggested that the absorption of bismuth increases when bismuth salts are used with ranitidine hydrochloride. The absorption and deposition of bismuth as a result of the use of the new drug ranitidine bismuth citrate have not been yet clarified. After 15 days of twice daily oral gavage with bismuth subcitrate, 13·7 mg kg^?1 day^?1 to eight rats, deposition of bismuth was found in all the tissues studied, especially the kidney (30·81 ± 8·59 μg g^?1 dry weight). A similar pattern of distribution and tissue concentrations was found when bismuth subcitrate was given with ranitidine hydrochloride 8·6 mg kg^?1 day^?1 to another eight rats, although this combination resulted in lower brain levels (3·12 + 1·31 μg g^?1 dry weight) than after administration of bismuth subcitrate alone (4·77 ± 0·97 μg g^?1 dry weight). When six rats were given ranitidine bismuth citrate by gavage at 22·8 mg kg^?1 day^?1 for 15 days, kidney levels were lower (4·24 ± 1·75 μg g^?1 dry weight) and brain levels were below detection limits; the bismuth concentrations in the faeces from this group were also significantly lower (1603 ± 104·0 μg g^?1 dry weight) than for the two other groups. After dosing with bismuth alone or in association with ranitidine hydrochloride, bismuth was detected in several organs and deposition was not influenced by gastric pH. Blood levels correlate poorly with organ deposition and brain deposition was not always associated with encephalopathy. After administration of ranitidine bismuth citrate, significantly lower concentrations of bismuth were found in the kidney and bismuth was not detectable in the brain, suggesting lower bismuth absorption. This was confirmed by higher levels in the faeces after dosing with ranitidine bismuth citrate. Thirty days after dosing with ranitidine bismuth citrate or bismuth subcitrate, bismuth could not be detected in any of the organs examined but could be found in the urine. In conclusion, bismuth was deposited in the kidney, brain, lung and liver of rats after oral dosing with bismuth subcitrate. After oral dosing with an equivalent amount of bismuth in the form of ranitidine bismuth citrate, significantly lower concentrations of bismuth were deposited in the kidney; in the brain bismuth was not detectable.     

Further studies on the in vivo effect of diisopropyl 1,3-dithiol-2-ylidenemalonate (NKK-105) on the liver microsomal drug oxidation system in rats

The effect of diisopropyl 1,3-dithiol-2-ylidenemalonate (NKK-105) on microsomal electron transport systems in relation to drug oxidation was studied in rat liver. A single oral dose (250 mg/kg) of NKK-105 increased the ratio of liver to body weight, the microsomal protein content, the cytochrome b₅ content, and the NADPH cytochrome c reductase activity at 24–48 hr after drug administration. The cytochrome P-450 content was decreased at 2–6 hr and slightly increased at 24–48 hr after drug administration. Upon daily administration of NKK-105 at a dose of 250 mg · kg^?1 · day^?1 for 21 days, cytochrome b₅ content and NADPH cytochrome c reductase activity were increased, but cytochrome P-450 content and NADH cytochrome b₅ reductase activity remained unchanged. Despite the increase of NADPH cytochrome c reductase activity, NADPH-dependent lipid peroxidation tended to decrease rather than increase. NADPH stearoyl-CoA desaturase activity increased prior to the increase of cytochrome b₅. Benzphetamine N-demethylase and p-nitroanisole O-demethylase activities were enhanced, accompanied by an increase of cytochrome b₅. Aniline hydroxylase activity was decreased by NKK-105 administration. These results indicate that the induction pattern of liver microsomal electron transport systems by NKK-105 is characteristic.     

Some biochemical aspects of the potential benefit of associating MD780515 with tricyclic antidepressants

In the rat, suitable oral doses of tricyclic antidepressants (amitriptyline 20 mg kg^?1, imipramine, desipramine 2·5 mg kg^?1) are able to antagonize the increase of cardiac levels of intravenous tyramine after a pharmacologically active dose (3·5 mg kg^?1 orally) of a reversible and specific type A MAO inhibitor, MD780515 (3-[4-(3-cyanophenyl-methoxy)phenyl]-5-(methoxymethyl)-2-oxazolidinone). MD780515, in oral doses up to 35 mg kg^?1, does not alter the liver microsomal drug metabolizing enzymes in the rat. Therefore, when given with tricyclic antidepressants, it should not interfere with their metabolism.