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PubMed1988

Age-associated stereoselective alterations in hexobarbital metabolism.

This clinical investigation was designed to study the influence of age on stereoselective drug disposition using hexobarbital as a model marker. The disposition of hexobarbital enantiomers was investigated in 10 young and 10 elderly, healthy male volunteers. Mean oral clearance (+/- SD) of d-hexobarbital (1.9 +/- 0.5 vs. 1.7 +/- 0.3 ml/min/kg; P greater than 0.05) did not differ significantly between the young and elderly subjects, respectively. However, despite wide intersubject variability, l-hexobarbital mean oral clearance (+/- SD) was approximately twofold greater in the young than in the elderly subjects (16.9 +/- 11.9 vs. 8.2 +/- 3.2 ml/min/kg; P less than 0.05). This resulted in a significantly greater enantiomeric oral clearance ratio in the young when compared with the elderly subjects (8.3 +/- 3.4 vs. 4.7 +/- 1.4; P less than 0.01). No significant difference (P greater than 0.05) in pharmacologic response after hexobarbital administration was found between the two groups. Demonstration of an age-related preferential decline in metabolism of one enantiomer over another has not been reported previously for any racemic drug in animals or humans.

Administration, Oral↗

PubMed1986

Interactions between hexobarbital and thiopental in male rats evaluated with an anaesthesia threshold.

The anaesthetic interaction between hexobarbital and thiopental in different combinations were investigated in male rats by using the isobolografic method. Data on dose, serum or brain concentrations at an EEG-criterion induced with a threshold method were utilized. The criterion was defined by a burst suppression in the EEG of 1 sec. or more (the "silent second"). With rats more than 115 days of age a synergistic interaction (potentiation) was obtained when a low dose of hexobarbital and a high dose of thiopental were used. The relationship between serum and brain concentrations of hexobarbital and thiopental in the different tested combinations gave no evidence for a pharmacokinetic interaction. Thus the synergistic interaction was located in the brain and probably related to the mechanisms of action. The same tests performed on rats at an age of approximately 90 days gave not only a potentiation when a low dose of hexobarbital and a high dose of thiopental were used, but also a potentiation when a high dose of hexobarbital and a low dose of thiopental were used. These results indicate an age-related change in sensitivity in the CNS between 90 and 115 days of age. Further investigations of this age-related change showed that this change from a potentiation to an additive interaction occurred between the age of 85 and 96 days.

Anesthesia↗

PubMed1975

Effect of dietary rapeseed oil on hepatic hexobarbital metabolism in mice.

The effect of dietary rapeseed oil (RSO) on hepatic hexobarbital metabolism has been studied in short-term experiments in mice by measuring both the activity of mixed function oxidase system in microsomal preparations in vitro and the in vivo hexobarbital-induced sleeping time. Moreover, the fatty acid pattern of liver tissue, with particular regard to erucic and gadoleic acids, was analyzed gas-chromatographically. The hexobarbital metabolism in young RSO-fed (RSO containing 52% of erucic acid and 7.4% of gadoleic acid; 50 cal% for 3 days) is lower by about 44% than in controls treated in the same way with peanut oil, independently of sex. RSO did not have a statistically significant effect of hexobarbital metabolism in adult animals of both sexes. As to the dose-response study, the prolongation of the hexobarbital-induced sleeping time in young male is statistically significant when fed with 30 cal% in RSO for 3 days, while it is not more statistically significant in mice fed 15 cal% in RSO. In RSO mice (50 cal%) erucic and gadoleic acid account both for about 10% of the total fatty acids in the liver tissue, while they are quite absent in controls. It causes a relative deficiency of linoleic and arachidonic acids, known to be essential for synthesis and maintenance of the membranes supporting hepatic microsomal enzymes responsible for the metabolism of some drugs.

Animals↗

PubMed1993

Phenytoin induction of cytochrome P4502B in mice: effects on hexobarbital hydroxylase activity.

1. Treatment of ICR and C57BL/6 mice with phenytoin (50 mg/kg, i.p., 3 days) resulted in approximately 33 and 43% increases in hepatic cytochrome P450 levels relative to uninduced microsomes, respectively. Phenytoin treatment caused a 63% decrease in hexobarbital sleeping time in ICR mice (19 versus 52 min). 2. Both Western immunoblot analysis and solid phase radioimmunoassay using monoclonal anti-rat P4502B antibody showed that P4502B was increased significantly in phenytoin-induced mouse microsomes compared with uninduced mice. P4502B9 was the predominantly induced form whereas 2B10 was elevated marginally. Phenytoin was as efficacious as phenobarbital in increasing P4502B. 3. Phenytoin treatment resulted in an approximately 8-fold increase in hexobarbital hydroxylase activity whereas phenobarbital treatment caused an approximately 13-fold increase. Addition of anti-P4502B antibody produced complete inhibition of hexobarbital oxidation in phenytoin-induced microsomes, indicating that raised P4502B in phenytoin-induced microsomes is associated with the increased hexobarbital hydroxylase activity. 4. Phenytoin failed to increase P4501A in either C57BL/6 or ICR mice, as assessed by both immunoblot analysis and metabolic activities. Although both aryl hydrocarbon hydroxylase and 7-ethoxycoumarin deethylase activities were raised approximately two-fold following phenytoin treatment, the metabolic activities were not inhibited by anti-P4501A antibody. 5. These results provide evidence that phenytoin induces P4502B in mice with pronounced increase in hexobarbital hydroxylase activity, and fails to induce P4501A in either C57BL/6 or ICR mice.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1975

Influence of cystamine on activity and biotransformation of hexobarbital.

Influence of cystamine on hypnotic potency and biotransformation of hexobarbital in rats was studied. Duration of hexobarbital-induced sleep was prolonged maximally by 42% on the first day after premedication, and by 37% on the third day. After six days, differences from the control group were within the limits of experimental error. Biotransformation of hexobarbital was only slightly inhibited in rats premedicated with cystamine, confirmed by determinations of hexobarbital oxidase activity. Excretion of hexobarbital and its metabolites was delayed.

Animals↗

PubMed1992

[Drug clearance as a decision aid for further invasive liver diagnosis--studies with hexobarbital as a model substrate].

The clearance of a drug predominantly metabolized in the liver may serve as an estimate of quantitative liver function. In 260 consecutive patients presenting with a history of liver disease and abnormal laboratory findings but without a current definite diagnosis we have measured the clearance of hexobarbital and investigated if low values in patients are able to support the decision for an invasive diagnostic procedure such as needle biopsy or laparoscopy. 250 mg of hexobarbital was given orally to the patients between 8 and 10 hrs p.m. 12 hrs later blood samples were taken. Hexobarbital was determined by gas chromatography with N-selective detection, and a single point clearance was calculated. We recommended liver biopsy or laparoscopy to all patients with a hexobarbital clearance below 2.7 ml/min/kg body weight (normal 2.66-5.34 ml/min/kg). 73 out of 260 patients showed a reduced hexobarbital clearance. In 44 patients blind liver biopsy (n = 14) or laparoscopy (n = 30) was performed, 29 patients refused an invasive diagnostic procedure. 17 out of 26 patients with the tentative diagnosis chronic hepatitis had already an incomplete or complete liver cirrhosis. In 11 out of 18 patients with the tentative diagnosis alcohol toxic liver injury we found a progressive portal fibrosis or complete liver cirrhosis. Reduced drug clearance reflecting quantitative liver function can be an indicator of advanced liver disease, thus adding substantially to the decision for further invasive diagnostic procedures.

Cytochrome P-450 CYP11B2↗

PubMed1989

[Effect of vephylline on hexobarbital metabolism after single and multiple administrations].

The purpose of the present study is to evaluate the influence of a new Bulgarian original preparation Verphyline on hexobarbital metabolism. The studies were carried out on white male rats of Wistar strain after single and multiple administrations. After single administration Verphyline prolongs the duration of hexobarbital sleep (HBS), which accompanies elevated serum concentrations of hexobarbital (S-HB) and inhibits the activity of hexobarbital oxidase (HBO). After a 4-day period of treatment with Verphyline shortening of HBS is observed, reduction of sera levels of hexobarbital and activation of HBO. Biotransformation of the examined preparation is most probably connected with liver microsomal enzymic systems and changes of their activity after multiple applications.

Aminophylline↗

PubMedDate not supplied

Studies on the cause of changes of reactivity to hexobarbital in spontaneously hypertensive rats (SHR).

The hypnotic action of hexobarbital is weaker in spontaneously hypertensive rats (SHR) than in Wistar rats. The difference does not appear in young rats (up to the sixth week of life) and appears gradually concomitantly with maturation of animals. There was no correlation between the changes of reactivity to hexobarbital and development of hypertension. The rate of metabolism of hexobarbital was similar in SHR and Wistar rats. There is a close relationship between the changes in reactivity to hexobarbital and psychomotor activity: both are significantly higher in SHR than in Wistar rats. The results suggest that the main cause of a weaker action of hexobarbital in SHR is higher intensity of stimulatory processes in the central nervous system.

Aging↗

PubMed1978

Effect of subacute intoxication with some heavy metals on hexobarbital sleep and metabolism.

In experiments on albino rats it is found that cobaltous dichloride, cadmium nitrate, nickel sulphate, copper sulphate and lead acetate, applied subcutaneously for 7 days, potentiate hexobarbital anaesthesia, while mercury dichloride and iron dichloride have no effect on it. A higher hexobarbital content is found in the blood serum of rats, treated with cobaltous dichloride, cadmium nitrate, nickel sulphate, copper sulphate and lead acetate, compared with the control animals. Treatment for 7 days with cobalt dichloride, cadmium nitrate, copper sulphate and nickel sulphate inhibits the activity of the liver microsomal hexobarbital-oxidizing enzyme system. The prolonged hexobarbital sleep in rats subjected to subacute intoxication with cobalt, cadmium, nickel, copper and lead is probably due to a considerable extent to the inhibition of the hexobarbital metabolism by these metals.

Animals↗

PubMed1976

[Sleeping time and awaking blood concentration of hexobarbital influenced by glucose and adrenaline in rats of both sexes].

Sleeping times in male and femal rats are prolonged after the simultaneous i.p. administration of adrenaline and hexobarbital sodium. The blood concentration of hexobarbital at awakening is unchanged in male rats, while in females this concentration is decreased. When adrenaline is given s.c., no change in sleeping times is observed in female and male rats, while the blood concentration of hexobarbital for the two sexes is decreased. Glucose, given p.o. or i.p., has no influence on sleeping times or on hexobarbital concentrations. The hexobarbital concentrations at awakening is higher in female than in male rats.

Animals↗

PubMed1985

Selected ion monitoring analysis of pseudoracemic hexobarbital and its major metabolites in blood and urine of rats.

A stereospecific synthesis of N1-(2H3)-labelled R(-)-hexobarbital is described. A sensitive and rapid selected ion monitoring assay procedure for pseudoracemic hexobarbital, consisting of equal amounts of S(+)-hexobarbital (1a) and (2H3)-R(-)-hexobarbital (1b) in 100 microliters blood samples of rats was developed. Both the parent enantiomers in blood and three major metabolites excreted in urine were quantified. An application of the method in rats is described, and the results are compared to previously obtained data of separately administered enantiomers.

Animals↗

PubMed1980

Disposition of hexobarbital in intra- and extrahepatic cholestasis in man and the influence of drug metabolism-inducing agents.

The pharmacokinetics of intravenously infused hexobarbital was studied in 10 patients with intrahepatic cholestasis and in 9 with extrahepatic biliary obstruction. The results were compared with those obtained in 16 healthy young volunteers and 5 older patients with normal liver function. After infusion, the plasma concentrations showed a rapid initial decline (alpha-phase) and subsequently a slower decrease (beta-phase). The half-life of a latter phase was 323 +/- 84 min in the healthy group, 357 +/- 151 min in the patients with intrahepatic cholestasis and 344 +/- 115 min in the group with biliary obstruction; the clearances were 3.41 +/- 0.90, 4.08 +/- 1.95 and 3.81 +/- 1.97 ml x min-1 x kg-1, respectively. The differences were not statistically significant. The mean volume of the central compartment of distribution and the steady state volume of distribution were not significantly different. In two patients hexobarbital clearance during cholestasis was greater than after it had subsided. After treatment of 11 patients with cholestasis with drug metabolism-inducing agents (phenobarbital, rifampicin or phenytoin), the half-life of hexobarbital was significantly shortened and the mean value of hexobarbital clearance was more than doubled.

Adult↗

PubMed1987

Kinetics of hexobarbital and dipyrone in critical care patients receiving high-dose pentobarbital.

The effect of pentobarbital treatment in a mean dose of 30 mg/kg/day on the clearance of hexobarbital (Evipan) and dipyrone (Novalgin) has been evaluated in critical care patients receiving a large number of drugs as comedication. Eleven patients treated with pentobarbital showed a hexobarbital half-life of 2.79 h and a total plasma clearance of 9.80 ml X min-1 X kg-1 as compared to 10 patients without pentobarbital administration in whom there was a significantly longer half life (6.92 h) and lower clearance (2.97 ml X min-1 X kg-1). The kinetics of hexobarbital were correlated with the urinary excretion of D-glucaric acid, a non-invasive parameter of drug metabolising activity. In 10 patients on pentobarbital, the total plasma clearance of N-4-methyl-aminoantipyrine, the active form of dipyrone, did not differ from that in 8 patients not receiving pentobarbital. As drug kinetics show great variability in these patients, it is difficult to discriminate enzyme induction from other mechanisms, for example competitive inhibition or changes in volume of distribution. In the presence of pentobarbital, however, induction of drug metabolising enzymes should be considered as a possible reason for the higher clearance of hexobarbital.

Adult↗

PubMed1984

Different interactions of steric isomers of hexobarbital to muscarinic agonist and antagonist binding sites in brain.

The interaction between the racemate, or the steric isomers of hexobarbital, and the binding of [3H]oxotremorine or [3H]quinuclidinylbenzilate to muscarinic binding sites was studied in different parts of the rat brain. In concentrations clearly within those reached when inducing anesthesia, hexobarbital displaced both the agonist and the antagonist from their binding sites. (-)-R-hexobarbital, which is least potent as an anesthetic, was most potent as a displacer. In most brain regions, the agonist was more readily displaced than the antagonist by both isomers of hexobarbital.

Anesthesia, General↗

PubMedDate not supplied

Dynamic aspects on acute tolerance to hexobarbital evaluated with an anesthesia threshold.

Induction of acute tolerance was studied with hexobarbital in male rats. A threshold technique utilizing an EEG-criterion consisting of a burst suppression of 1 second or more (the SS) was used both to induce and maintain anesthesia. Hexobarbital was infused with an optimal dose rate of 15 mg/kg/min. The infusion was stopped at the criterion and restarted when no SS had been seen for 1 min. The doses of hexobarbital needed to maintain anesthesia were fairly constant around 3.5 mg/kg/min up to durations of 120 min which indicates that redistribution of hexobarbital is of minor importance in the present experiments. After different predetermined times of this fairly stable anesthesia, the rats were sacrificed, and concentrations in the cortex of the brain were determined with a HPLC-method. Maximal induction of acute tolerance was seen as a 45 percent increase in cortex concentration after 60 min of anesthesia, but already after 10 min a slight acute tolerance was recorded.

Anesthesia, Intravenous↗

PubMed1998

A study of the duration of acute tolerance induced with hexobarbital in male rats.

Male rats were infused i.v. with hexobarbital to obtain a burst suppression of 1 s or more in the EEG (SS). At SS the rats were killed and the concentration of hexobarbital was determined by HPLC in three parts of the brain. Acute tolerance (induced by a 1-h exposure at the SS level) was recorded as an approximately 20% increase in brain concentrations of hexobarbital at the last SS during the exposure when compared with concentrations recorded at the first SS in the controls. Increased brain concentrations (approximately 8%) at SS were recorded 24 h after induction of acute tolerance. After 48 h the increase was uncertain. Thus, acute tolerance to hexobarbital could have cumulative properties if new exposures are imposed after 24 h.

Animals↗

PubMed1976

Effect of water and food deprivation on hepatic microsomal metabolism of hexobarbital and aniline.

Water deprivation for 48 hr with its accompanying decrease in food intake significantly lowered the in vitro rate of hexobarbital metabolism by hepatic microsomes isolated from male rats. Pair-fed rats allowed water ad libitum had a significantly lower level of hexobarbital metabolism than those deprived of water. Rats starved for 24 hr with or without water also had levels of hexobarbital metabolism significantly lower than their controls; with those animals allowed water ad libitum, the level was significantly lower than for those deprived of water. In vivo hexobarbital "sleeping time" experiments were in general agreement with these results. The in vitro metabolism of aniline was increased in both male and female rats following 24 hr starvation and in female rats (but not males) the effect was greater when water was allowed than when deprived. The differences between hydrated and dehydrated animals were not attributable to reduction in concentration of microsomal protein or the water content of liver. It is concluded that water consumption accentuates the effect of food deprivation on hepatic microsomal metabolism.

Aniline Compounds↗

PubMed1985

Direct effect of carbon monoxide on hexobarbital metabolism in the isolated perfused liver in the absence of hemoglobin.

The interaction of carbon monoxide (CO) with cytochrome P-450 associated with hexobarbital metabolism was observed in hemoglobin-free perfused rat liver by using a scanning reflectance spectrophotometer. The evidence obtained showed that CO bound to the substrate complexed cytochrome P-450 and, at a CO/O2 ratio of over 0.1 in the perfusate, inhibited the hexobarbital metabolism estimated from the hexobarbital uptake, and oxygen consumption. Although the oxygen supply to the liver cell was one of the major limiting factors during CO hypoxia, CO binding to cytochrome P-450 significantly enhanced the suppression of hexobarbital oxidation caused by hypoxic hypoxia.

Animals↗