• The Korean Journal of Pharmacology
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• v.22 no.2
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• pp.88-95
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• 1986

Clinically, subhypnotic doses of barbiturates have been known to elicit hyperalgesia. In this experiment, effect of acute or chronic phenobarital treatment on the response to pain in rat was reevaluated by hot-plate method. To elucidate its mechanism, changes of ${\beta}-endorphin$ contents and [3H]-morphine binding of the rat midbrain as well as functional opiate receptor in vas deferens were also measured. Intraperitoneal injection of sub anesthetic dose phenobarbital induced initial hyperalgesia followed by successive analgesia, while chronic phenobarbital-treatment decreased reactivity to pain. Naloxone (10mg/kg, i.p.) markedly shortened hot plate latency period, and significantly inhibited the analgesic action of phenobarbital. Single dose of phenobarbital did not affect ${\beta}-endorphin$ contents and [3H]-morphine binding in rat mid brain, but in the chronic phenobarbital-treated groups, ${\beta}-endorphin$ contents was increased, while Bmax of opiate receptor binding was decreased. Moreover, very significant correlations among responses to pain, changes of ${\beta}-endorphin$ contents and opiate receptor binding were observed. However, Kd values of opiate receptor bindings were not changed in all preparations. In the chronic phenobarbital-treated vas deferens preparations, ID50 of morphine was increased witb concomittant decrease of maximum effect. But $pA_2 $, value for naloxone was not changed. From these results, it is suggested that phenobarbital can produce analgesia due to changes of ${\beta}-endorphin$ contents as well as functional opiate receptors by receptor regulation.

• Journal of Pharmaceutical Investigation
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• v.8 no.2
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• pp.11-17
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• 1978

Phenobarbital의 용출속도(溶出速度)를 증가시키기 위하여 PVP와의 공침물(共沈物)을 형성(形成)한 후 일정(一定)한 표면적(表面積)하에서의 용출속도(溶出速度)를 비교검토(比較檢討)하였다. $37^{\circ}C$, 150r.p.m${\times}$에서의 rate constannt of dissolution, k,는 phenobarbital이 $8.75{\times}10^{-6}M/min$, 1 : 2 phenobarbital-PVP coprecipiate는 $5.35{\times}10^{-5}M/min$이었으며, activation energy of dissolution, Ea는 phenobarbital이 약 10,600cal/mole coprecipitate는 약 5,800cal/mol이었다. 그리고 X-ray diffraction study에 의(依)하면 페노바르비탈 단일물질(單一物質)이나, PVP와의 physical mixture에서는 페노바르비탈의 결정피크를 나타내었으나, PVP와의 공침물(共沈物)의 경우(境遇)에는 페노바르비탈의 결정피크를 인지(認知)할 수 없었다.

• The Korean Journal of Pharmacology
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• v.18 no.2
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• pp.51-58
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• 1982

In this paper, the influence of phenytoin and phenobarbical on the changes of brain norepinephrine(NE) content, plasma corticosterone and blood sugar level in mice were studied. The results obtained were summarized as follows: 1) Phenytoin(50 mg/kg) increased the brain NE content but phenobarbital(50 mg/kg) did not affect. The increase of the brain NE content induced phenytoin was potentiated by phenobarbital pretreatment. 2) Phenytoin(25 mg/kg, 50 mg/kg) markedly increased the level of plasma corticosterone but phenobarbital did not affect. The increase of the plasma corticosterone induced by phenytoin was inhibited by phenobarbital pretreatment. 3) Phenytoin(50 mg/kg) markedly increased the blood sugar level but phenobarbital did not affect. The increase of the blood sugar induced by phenytoin was not affected by phenobarbital pretreatment.

• Archives of Pharmacal Research
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• v.15 no.1
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• pp.78-86
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• 1992

The induction of hepatic cytochromes P450 and metabolic effects have been examined in male and female Sprague-Dawley rats following treatment with either phenobarbital or 3-methylcholanthrene. Hepatic cytochrome P450 levels were higher in males than in females by ~40%. Treatment of male and female rats with phenobarbital or 3-methylcholanthrene resulted in an ~1.6 and 2-fold increase, respectively, in heptic microsomal cytochrome P450 levels in both sexes, relative to untreated animals. Immunoblot analyses were performed to compare sex-related changes in P450 levels. Hepatic P45IIB1 levels in males were greater than those in females following phenobarbital treatment. 3-Methylcholanthrene-induced male hepatic microsomes exhibited greater levels of P450 females failed to exhibit a band. Mab PCN 2-13-1 against P-45-IIIA recognized an intense in uninduced microsomes from female rats. The levels of P450IIIA in males were increased 2 to 3-fold following treatment with phenobarbital, while the increase of IIIA levels in females by phenobarbital was minimal, as monitored by immunoblot analysis. Solid phase radiommunoassay using monoclonal antibodies supported the results of immunoblot analysis. Phenobarbital treatment caused a 6.5-fold increase in the monoclonal iantibody binding to IIBI in males, whereas treatment of females with phenobarbital resulted of IA levels by 3-methylcholanthrene was also greater in females than in males (10-vs. 8-fold) although the levels of induced IA were comparable inboth sexes, as assessed by radiommunoassay. Radioimmunoassay also showed that hepatic IIEI level was 1.5-fold higher in males than in females and that either phenobarbital or 3-methylcholanthrene treatment caused 80% to 40% decrease in IIEL levels, relative to control, in both sexes. Sex-related metabolic activities were examined in hepatic microsomes. Hexobarbital hydroxylase activity was 2-to 3-fold higher in uninduced microsomes from males than that from females. This hydroxylase activity was increased 2-and 3-fold in males and females, respectively, following phenobarbital treatment, as compared to controls. Addition females produced 64% and 84% inhibition of hexobarbital oxidation, respectively. Aryl hydrocarbon hydroxylase activity was increased -12 and 26-fold in males and females respectively. Following phenobarbital treatment, as compared to controls. Addition of anti-P450IIB1 antibody to phenobarbital-induced hepatic microsomes from males and females produced 64% and 84% inhibition of hexobarbital oxidation, respectively. Aryl hydrocarbon hydroxylase activity was increased -12 and 26 fold in males and females, respectively, following 3-methylcholanthrene treatment relative to controls. The anti-P-450IA antibody inhibitable rate of aryl hydrocarbon hydroxylase activity was comparable in both sexes following 3-methylcholanthrene treatment relative to controls. The anti-P450LA antibody inhibitable rate of aryl hydrocarbon hydroxylase activity was comparable in both sexes following 3-methylcholanthrene treatment (-70%). These results demonstrate that levels of hepatic P450IIB1 or P450IA are greater in male than in female for untreated, phenobarbital-or-3-methylcholanthrene treated rats. In addition, the relative for untreated phenobarbital-or 3-methylcholanthrene treated rats. In addition, the relative increase of phenobarbital-or 3-methylcholanthrene treated rats. In addition, the relative increase of phenobarbital-or 3-methylcholanthrene treated rats. In addition, the relative increase of P450IIB1 or IA phenobarbital or 3-methylcholanthrene is more significant in females.

• Journal of Preventive Medicine and Public Health
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• v.35 no.3
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• pp.229-235
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• 2002

Objectives : To evaluate the effects on the formation of benzidine-hemoglobin, and benzidine metabolite-hemoglobin adducts, caused by pretreatment with the known xenobiotic metabolism effectors, ethanol and phenobarbital, in rats administered Direct Black 38 dye. Methods : The experimental rats were divided into three groups: a control group, an ethanol group and a phenobarbital group. Rats were pretreated with ethanol (1g/kg) or phenobarbital (80mg/kg) 24 hours prior to the oral administration of Direct Black 38 (0.5mmol/kg), with the control group being administered the same amount of distilled water. Blood samples were obtained from the vena cava of 5 rats from each group prior to, and at 30 min, 3h, 5h, 9h, 12h, 24h, 48h, 72h, 96h, and 144h following the oral administration of Direct Black 38. Directly after sampling the blood was separated into hemoglobin and plasma, with the adducts being converted into aromatic amines by basic hydrolysis. Hydrolyzed benzidiene, monoacetylbenzidine and 4-aminobiphenyl were analyzed by reverse-phase liquid chromatography with an electrochemical detector, The quantitative amount of the metabolites was expressed by the hemoglobin binding index (HBI). Results : In the ethanol group, benzidine-, monoacetylbenzidine-, and 4-aminobiphenyl-HBI were increased to a greater extent than those in the control group. These results were attributed to the ethanol inducing N-hydrgxylation, which is related to the formation of the hemoglobin adduct, In the phenobarbital group, all the HBIs, with the exception of the benzidine-HBI, were increased to a greater extent than those of the control group. These results were attributed to the phenobarbital inducing N-hydroxylation related to the formation of the hemoglobin adduct. The N-acetylation ratio was only increased with the phenobarbital pretreatment due to the lower benzidine-HBI of the phenobarbital group compared to these of the control and ethanol groups. The N-acetylation ratios for all groups were higher than f for the duration of the experimental period. Although the azo reduction was unaffected by the ethanol, it was inhibited by the phenobarbital, The ratio of the benzidine-HBI in the phenobarbital group was lower than those of the ethanol the control groups for the entire experiment. Conclusion : Our results indicate that both ethanol and phenobarbital increase the formation of adducts by the induction of N-hydroxylation, but also induced N-acetylation. Phenobarbital decreased the formation of benzidine-HBI due to the decrease of the azo reduction. These results suggest that the effects or ethanol and phenobarbital need to be considered in the biochemical monitoring of Direct Black 38.

• Toxicological Research
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• v.6 no.1
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• pp.51-59
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• 1990

Effects of altering hepatic mixed-function oxidase (MFO) enzyme activities on the metabolism and acute toxicity of parathio were investigated in adult female rats. In vitro hepatic metabolism of parathion to paraoxon was increased by phenobarbital pretreatment (50 mg/kg/day, ip, for 4 consecutive days) and SKF 525-A (50 mg/kg, ip, 1 hr prior to sacrifice) decreased paraoxon formation indicating that phenobarbital induces that form(s) of cytochrome P-450 catalyzing conversion of parathion to paraoxon. Degradation of paraoxon to p-nitrophenol was increased by phenobarbital pretreatment, but not affected by SKF 525-A suggesting that MFO activities play only a minor role in the detoxification of the active metabolite of this insecticide. The phenobarbital-induced increase in paraoxon formation was partially antagonized by SKF 525-A. Significant activity for both parathion activation and paraoxon degradation was also observed in the lung preparation, however, this extrahepatic parathion and paraoxon metabolizing activity was not induced by phenobarbital or inhibited by SKF 525-A pretreatment. Phenobarbital pretreatment increased paraoxon level in livers of rats when measured 3 hr following parathion injection (2 mg/kg, ip). SKF 525-A did not alter parathion or paraoxon levels in brain, blood and liver. Phenobarbital pretreatment decreased the toxicity of parathion (4mg/kg, ip) or paraoxon (1.5 mg/kg, ip) as determined by decreases in lethality and inhibition of brain and lung acetylcholinesterases. An additional SKF 525-A treatment failed to decrease the protective effects of phenobarbital against parathion or paraoxon toxicity. These results suggest that some unknown factors other than hepatic MFO induction are involved in the protective action of phenobarbital against parathion and paraoxon toxicity.

• YAKHAK HOEJI
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• v.30 no.6
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• pp.288-293
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• 1986

Effects of phenobarbital on the pharmacokinetics of griseofulvin were studied in rats. Phenobarbital was administered orally for five days at the dose of 75mg/kg/day. Absolute bioavailability of oral griseofulvin was significantly(p<0.005) reduced but total clearance(CL$_s$ was not changed by phenobarbital pretreatment. Absorption rate constant(K$_a$ and maximum plasma concentration(C$_{max}$) were significantly(p<0.05) reduced, and time to reach maximum plasma concentration(T$_{max}$) of griseofulvin was significantly(p<0.05) increased by phenobarbital pretreatment. Changed pharmacokinetics of griseofulvin seemed not to be due to induced enzyme activity by phenobarbital but to reduced GI absorption of griseofulvin.

• YAKHAK HOEJI
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• v.16 no.4
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• pp.155-161
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• 1972

The hydrolysis of phenobarbital is decelerated in alkaline solution by betacyclodextrin. The betacyclodextrin inhibits the degradation of phenobarbital up to 1.5 fold in the system containing 1% betacyclodextrin. The degradation mechanism in systems containing betacyclodextrin is the same that in system without complexing agent, although the rate constants are different. The pH dependence of the hydrolysis rate deceleration is compared with the ionization percent of betacyclodextrin. The results indicate that a direct relationship does not exist between the ionization of betacyclodextrin. It seems reasonable therefore that the phenobarbital undergoes a stable complex with betacyclodextrin and complex formation would provide a better shield for the phenobarbital from hydroxyl ion attack.

• Journal of Pharmaceutical Investigation
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• v.17 no.1
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• pp.15-21
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• 1987

Effects of phenobarbital pretreatment on the pharmacokinetics of enterohepatic recirculating griseofulvin were investigated by comparing normal to bile duct cannulated rats and also the effects of enhanced endogeneous bile flow on the absorption of griseofulvin were studied by means of in situ recirculation method in phenobarbital-pretreated rats. Phenobarbital was administered orally for five days at the dose of 75 mg/kg/day. The influence of phenobarbital pretreatment on the absorption rate constant, area under the plasma concentration-time curve, maximum plasma concentration of orally administered griseofulvin was not found in bile duct cannulated rats. Decreased absorption clearance and apparent partition coefficient of griseofulvin in accordance with the amount of endogeneous bile juice seemed to be due to the decrease of thermodynamic activity of griseofulvin as bile forms the micelle with griseofulvin.

• The Korean Journal of Pharmacology
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• v.11 no.1 s.17
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• pp.47-53
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• 1975

The metabolism of many drugs and also of steroid hormones is mediated by enzymes located in the microsomal fraction in smooth surfaced endoplasmic reticulum of mammalian liver. The duration and intensity of action of many drugs are largely determined by the speed at which they are metabolized in the body. Repeated administration of phenobarbital results in the induction of enzymes that metabolize a number of drugs. Lee et al. reported that daily administration of phenobarbital in rats significantly increased the activities of amylase in the pancreatobiliary juice, but the concentration of cholate in the bile was significantly lower in the treated group than that in the control group. After animals were treated with $CCl_4$, histological changes were shown in the endoplasmic reticulum, decreased microsomal enzyme activity and decreased hepatic protein synthesis were apparent. The purpose of the present report was to study the interaction between a 'microsomal-stimulating' agent such as phenobarbital and a 'microsomal- depressing' agent such as $CCl_4$ on hepatic and pancreatic functions in rats. The results obtained are summarized as follows: 1. The mortality rate of $CCl_4$ treated group was 34% and was decreased this figure to 15% with phenobarbital pretreatment. 2. In animals treated with phenobarbital the volume of biliary-pancreatic secretion was markedly elevated but the volume was decreased significantly in animals treated with $CCl_4$. 3. Total bilirubin output was elevated markedly in the $CCl_4$ treated group of rats pretreated with phenobarbital. The bilirubin concentration was increased in $CCl_4$ treated group and decreased in the group treated phenobarbital alone. 4. The concentration and total output of cholate in the bile were significantly lower in the all experimental group than control group. 5. In the animals treated with phenobarbital alone and phenobarbital plus $CCl_4$, the activity of lipase in pancreatobiliary juice was elevated, while in the animals treated with $CCl_4$ alone no change was observed. 6. The activity of amylase in the pancreatobiliary juice was decreased in the $CCl_4$ treated group, but elevated markedly in phenobarbital group and also elevated in phenobarbital-$CCl_4$ group. By the above results, it is concluded, when the liver was damaged by $CCl_4$, the exocrine function of pancreas and liver was decreased simultaneously. However, in the animals pretreated with phenobarbital, the toxicity of $CCl_4$ on the liver and pancreas was reduced.