SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
In rats the hexobarbital metabolism is impaired after different surgical procedures leading to muscle damage. This leads to a prolongation of the hexobarbital action. The prolonged effect of hexobarbital in rats with lymphostatic encephalopathy is considered an unspecific consequence of the tissue damage during lymphectomy.
Sensitivity of the central nervous system (CNS) to the hypnotic effect of hexobarbital was assessed by analytical, pharmacokinetic, and electroencephalographic techniques in male and female rats and in mice of both sexes by the first two techniques. These experimentally and conceptually diverse measures yielded strikingly similar estimates of CNS sensitivity to hexobarbital which was independent of both species and sex, while well known species ans sex (rat) differences in duration of response to hexobarbital were demonstrated.
Pharmacokinetic parameters of hexobarbital were estimated in rats after hepatic portal infusion of a 10-mg dose. Infusion during 10 min resulted in an area under the blood concentration-time curve (AUC) of 556 +/- 83 micrograms.min/ml and a clearance of 83 +/- 13 ml/min.kg, whereas infusion of the same dose during 40 min resulted in values of 272 +/- 36 micrograms.min/ml and 169 +/- 30 ml/min.kg, respectively (mean values +/- SD, n = 3). Infusion during 15 and 20 min provided intermediate values. The decrease of the AUC and the increase of the blood clearance of hexobarbital following decreasing infusion rates clearly indicate nonlinear pharmacokinetics related to the hepatic inflow concentration of hexobarbital.
Two model substrates for oxidative hepatic enzyme activity, namely hexobarbital and aminopyrine, were simultaneously orally administered to rats, and blood concentrations of the substrates measured by g.l.c. The apparent intrinsic clearances of hexobarbital (Cl*int.HB) and of aminopyrine (Cl*int,AM) were correlated in untreated rats, and in rats pretreated with phenobarbital, 3-methylcholanthrene, polychlorinated biphenyls or carbon tetrachloride. Cl*int,HB and Cl*int,AM were both increased by phenobarbital and polychlorinated biphenyl pretreatment. Pretreatment with 3-methylcholanthrene had hardly any effect, and carbon tetrachloride caused a strong diminution of Cl*int.HB and Cl*int.AM. When the dose of aminopyrine was decreased, both Cl*int,HB and Cl*int,AM increased. This indicated that the primary metabolite of aminopyrine, monomethylaminopyrine, inhibits cytochrome P-450. The correlation coefficient for all clearance data was 0.92 (N = 36). It was concluded that both hexobarbital and aminopyrine are metabolized in vivo by the same or closely related cytochrome P-450 isozymes, and both may be used as model substrates in vivo for metabolic conversions primarily mediated by the major phenobarbital-inducible cytochrome P-450 subspecies.
The flow dependency of hepatic hexobarbital metabolism was examined in the isolated perfused rat liver. At low flow rates (0.5-1.0 ml/min/g of liver) hexobarbital clearance was found to depend on perfusion fluid flow, whereas at higher flow rates drug clearnace approached flow independence. Calculation of the in vivo hepatic blood flow rate suggested that hexobarbital metabolism in vivo should be highly dependent upon flow. Blood flow in the conscious rat was measured by use of radiolabeled microspheres during acute exposure to levels of hypoxic hypoxia (lowered pO2) or carbon monoxide which resulted in equal alterations in arterial oxyhemoglobin content (approximately 65% oxyhemoglobin). Hypoxic hypoxia (8% O2) caused a massive redistribution of flow away from the splanchnic area, resulting in a 45% decrease in hepatic blood flow. Carbon monoxide (500 ppm) was without significant effect on hepatic blood flow. These data would appear to explain the relatively greater inhibitory potency of hypoxic hypoxia on drug metabolism in vivo, since drug delivery to the liver is depressed by hypoxic hypoxia but unaffected by carbon monoxide exposure.
The influence of intracerebrally injected biogenic amines and cyclic AMP dibutyrate on duration of sleep induced with hexobarbital (50 mg/kg i.v.) in rats was studied. Duration of sleep was markedly prolonged by adrenaline, noradrenaline, dopamine, 5-hydroxydopamine and acetylcholine. Cyclic AMP dibutyrate injected 30 minutes before hexobarbital shortened time of sleep. The role of biogenic amines in hexobarbital-induced sleep is discussed.
Previous findings from our laboratory suggested a possible interaction of atrazine, bentazon and molinate with other environmental and/or occupational poisons. The aim of this research was to obtain further toxicological information by using phenobarbital-induced rats and to characterize the effects of these herbicides on the hepatic microsomal metabolism of xenobiotics. Acute experiments have shown that the LD50 is augmented by the barbiturate pretreatment when atrazine is used, remains unchanged in the case of bentazon, but is lowered when molinate is given. Recrystallized atrazine, in the absence of the wetting compounds, elicits the same acute toxicity found when animals are challenged with a commercial preparation. No significant sex-related differences have been observed. In long-term treatment with these toxicants, atrazine shortened the hexobarbital narcosis, but no effect was observed after administration of either bentazon or molinate. Further studies on hexobarbital sleeping time demonstrated that females are more susceptible than males to the narcotic effect of this compound. The induction-like effect of atrazine exposure has been confirmed, mainly in young animals. At the end of the sleeping time, the actual serum concentration of hexobarbital is practically the same, and is not related to the length of the sleeping time. The absence of behavioral alterations in the open field tests exclude possible neurological effects of the triazine herbicide. In conclusion, these data demonstrate that atrazine by itself induces the hepatic pharmacometabolic system, while its metabolites result less toxic than the parent compound. On the contrary, metabolic transformations render the toxic effects of bentazon more severe.
The anaesthetic effects of a benzodiazepine derivate, flurazepam, and the anaesthetic interaction between flurazepam and 2 barbiturates, thiopental and hexobarbital, were studied in male rats using an EEG-threshold method. The criterion of anaesthesia was defined by a burst suppression in the EEG of 1 sec or more (the "silent second"). The dose needed to induce the criterion was used as the threshold. The data on the interaction were evaluated with the isobolographic method. Flurazepam alone infused with different rates gave an almost V-shaped dose-rate curve. Convulsive activity was seen in all rats in connection with the EEG-criterion. The mortality during anaesthesia increased with increased infusion rates of flurazepam. The anaesthetic interaction between thiopental-flurazepam and hexobarbital-flurazepam was with low admixture of flurazepam, a pronounced potentiation. With increased admixture of flurazepam, an additive interaction with thiopental and flurazepam was obtained, whereas an antagonistic interaction was obtained with hexobarbital and flurazepam. Convulsive activity and mortality during anaesthesia in the interaction studies were only observed in tests where high admixtures of flurazepam were used.
To 4 male and 2 female subjects hexobarbital was applied orally at different times of the day: 2, 10, 18 h. Serum concentrations of hexobarbital were determined by HPLC procedure and the resulting pharmacokinetic parameters in a rotating iterative program. Application at 18 h resulted in a shorter invasion time, a higher maximum concentration and a delayed elimination; in addition, the AUC was elevated in relation to application at 2 or 10 h. In the 2 female subjects a different pattern was observed. The results lead to the assumption that application of hexobarbital is more effective in the evening than in the morning.
The preparation of four optical isomers of 3'-hydroxyhexobarbital [5-(3'-hydroxy-1'-cyclohexen-1'-yl)-1,5-dimethylbarbituric acid] is described. The absolute configuration of the four isomers were assigned as (3'S, 5 R) and (3'R, 5R) for alpha- and beta-isomers from (R)-(--)-hexobarbital, respectively. Some of these isomeric 3'-hydroxyhexobarbitals, which are formed in the reaction of hexobarbital with liver microsomal mono-oxygenase, are oxidized to 3'-oxohexobarbital [5-(3'-oxo-1'-cyclohexen-1'-yl)-1,5-dimethylbarbituric acid] by dehydrogenase localized in the soluble fraction of liver homogenates. Comparison of activities among the four isomers for 3-hydroxyhexobarbital dehydrogenase was made by use of enzymes from guinea pig and rabbit liver. It became evident that either enzyme had a quite different activity towards each optical isomer, and the configuration of the 3'-position of hydroxyhexobarbital was an important factor affecting the reactivity of enzyme; isomers with 3'S-configuration were preferentially dehydrogenated to enantiomers with 3'R-configuration. Both enzymes had the highest activity towards (3'S, 5R)-3'-(--)-hydroxy-(--)-hexobarbital, irrespective of their having specificity towards different types of substrates.
An improved column-chromatographic method was described for isolation and purification on preparative scale of a glucuronide from urine of rabbits administered (RS)-hexobarbital. The analytically pure preparation obtained was found to be a mixture of two glucuronides of diastereomeric 3'-hydroxyhexobarbitals. Rates of hydrolysis of the glucuronides were dependent on the enzyme preparations used as well as on the configuration of the substrate. For quantitative determination, the glucuronides were hydrolyzed completely by beta-glucuronidases from either Escherichia coli or abalone entrails under the conditions used. In vivo studies on the metabolism of (R)-(-)- and (S)-(+)-hexobarbital in the rabbit showed that the glucuronides excreted in 24-hr urine accounted for about 30% of the dose of each enantiomer, and that conjugation of the hydroxy isomers with glucuronic acid was so stereoselective that the isomers with S-configuration at the 3'-position were preferentially conjugated. There were almost no differences in the urinary metabolite profile between normal an PB-treated rabbits; however, a noticeable change was observed in recovery of unchanged (S)-hexobarbital after phenobarbital treatment.
The pharmacokinetics of hexobarbital and heptabarbital were studied after simultaneous oral administration to rats in order to correlate their rates of metabolism. Hexobarbital and heptabarbital were chosen for this purpose as model substrates because of their structural, pharmacokinetic as well as metabolic similarity. Blood concentrations were measured for 2 hr after administration by a capillary gas chromatographic method. In control rats (n = 8) elimination half-lives and intrinsic clearance values ranged between 13 to 28 min and 96 to 435 ml/min X kg for hexobarbital and between 8 to 21 min and 84 to 371 ml/min X kg for heptabarbital, respectively. A short-term pretreatment of rats (n = 7) with phenobarbital resulted in small but significant increases in the rates of metabolism of both barbiturates, whereas treatment of rats with 3-methylcholanthrene (n = 5) resulted in a reversed effect. Correlation of the elimination half-lives of the two drugs in all experiments was only weak (r = 0.70). The intrinsic clearance values reflecting enzyme activity in vivo, however, were found to correlate very strongly (r = 0.97). The results of this study suggest that an experimental approach, in which intraindividual differences are eliminated, appropriate kinetic parameters are studied and similarity of metabolic profiles are taken into consideration are preferable to the previously applied longitudinally designed correlation studies.
Studies were conducted in an effort to determine if a circadian rhythm in response of mice to hexobarbital could be evaluated employing dose-response curves. Results showed a circadian change in both the position and slope of the dose-response curves when evaluated at 0800, 1400, 2000 and 0200 hours. Sleep times were longer at 0800 hours and shortest at 0200 hours, in the dark period. Greatest differences between slopes of the curves were noted when 1400 and 0200 as well as 0800 and 2000 hours were compared. Slopes were significantly flatter during the dark cycle relative to the light cycle suggesting altered rates of disposition of the drug. Measurements of in vitro hepatic metabolism of hexobarbital, p-nitro-anisole and aminopyrine at 0200 and 1400 hours demonstrated a significant rhythm in oxidative drug metabolism with maximal activity at 0200 hours. The results show that a rhythm in the duration of action of hexobarbital in mice is dose-dependent and that this rhythm is inversely related to a similar rhythm in microsomal drug metabolism. The rhythm in response to this agent may be subserved by a rhythm in drug metabolism.
Experiments on albino mice and rats have shown that pantogam, a derivative of pantothenic acid, potentiates the hypnotic effects of hexobarbital and barbital and enhances the effect of subthreshold doses of hexobarbital. The drug inhibits the amphetamine action in the amphetamine hyperaction test without affecting hexobarbital and amphetamine metabolism, or without increasing the blood-brain barrier permeability for these compounds and barbital. Pantogam does not influence the intensity of ethylmorphine N-demethylation in liver homogenates and the content of cytochrome P 450 and b5 in liver microsomes.
Previous experiments had shown that carbon monoxide inhalation prolonged the in vivo response zoxazolamine. However, CO was clearly less potent than an equivalent level of hypoxia induced by inhalation of lowered O2 content (hypoxic hypoxia). The present study revealed that both CO and hypoxic hypoxia also prolonged the pharmacologic response to a drug of vastly different structure and site of action, i.e., hexobarbital. In this case, CO was approximately equipotent to hypoxic hypoxia in prolonging sleeping time. In spite of a number of significant effects of the two types of hypoxia on factors such as rate of peritoneal absorption, distribution into the brain and brain sensitivity to the drug, their relative potencies in prolonging sleeping time appeared to reflect adequately their relative effects on in vivo rate of metabolism. This conclusion was based on their equipotencies in decreasing the rate of disappearance of hexobarbital from the blood. The observation that hypoxia induced by CO had no greater effect on hexobarbital metabolism than hypoxia induced by oxygen deprivation suggests that the binding of CO to cytochrome P-450 is not important in drug metabolism in vivo. CO would appear to act solely by inducing tissue hypoxia.
Rat livers were perfused with a red blood cell-containing perfusion medium. The rate of metabolism of hexobarbital was determined in this system as the recirculating perfusion fluid was made hypoxic by exposure to either CO or lowered oxygen tension. It was found that 7.6% of the total oxygen consumed by the liver was utilized to metabolize hexobarbital regardless of the severity of the hypoxia, which suggests that the liver does not shunt O2 to more preferential pathways as O2 availability becomes limited. When oxygen delivery was lowered below 0.3 ml of O2 per min per g of liver by either type of hypoxia, the rate of hexobarbital metabolism decreased. However, based on the rate of oxygen delivery, CO was more potent than hypoxic hypoxia in inhibiting drug metabolism. On the other hand, the two types of hypoxia were equipotent when compared on the basis of alterations in oxygen consumption. These results are consistent with the known effect of CO in decreasing the availability of hemoglobin-bound O2 and further argue against the direct inhibition of drug metabolism by the binding of CO to cytochrome P-450 in the isolated liver. They also suggest that the lack of a greater potency of CO relative to hypoxic hypoxia in vivo might be related to alterations in hepatic blood flow.
In experiments on albino rats of both sexes it has been established that hydrocortisone applied in a single dose of 50 mg/kg i.p. inhibits hexobarbital oxidase and ethylmorphine-N-demethylase and applied repeatedly in a dose of 10 mg/kg increases the activity of both enzymes. In castrated male rats the enzyme-inhibiting action of the single dose of hydrocortisone is much reduced, while its enzyme-inducing action on repeated application remains the same (the two effects are evaluated by the hexobarbital sleeping time).
The plasma levels of hexobarbital in humans were determined during and after a 30-min or 60-min zero-order intravenous infusion. Hexobarbital kinetics could be described by conceiving the body to exhibit two compartments. The plasma concentrations were fitted to the postinfusion equation and the parameters intrinsic to the two-compartment open model were estimated. The elimination half-life varied considerably among the 14 individuals (160-441-min), which could mainly be explained by the greatly varying metabolic clearance of the compound (123-360 ml/min). The apparent volume of distribution per kilogram of body weight was relatively constant (1.10 plus or minus 0.12 liters/kg).