Biomedical subjects
Publications and source records attributed to D D Breimer.
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16 patients with acute hepatitis, 18 patients with cirrhosis and a total of 21 volunteers and patients with normal liver function received 7.32 mg/kg hexobarbital by linear intravenous infusion within 60 min. Hexobarbital was determined gaschromatographically in serial blood samples and the hexobarbital-clearance was calculated from the plasma concentration curve versus time. Additional experiments were performed in rats suffering from so called "galactosamine hepatitis". In half of the patients with acute hepatitis a normal hexobarbital clearance could be found. In the other patients this was distinctly reduced but not correlation was found to other liver function tests. Patients with cirrhosis were subdivided into two groups. The patients in group 1 were well compensated. The patients in group 2 had a decompensated state with ascites and oesophageal varices. In nearly all patients with cirrhosis the hexobarbital-clearance was diminished. This was more pronounced in group 2. Ketohexobarbital excretion in healthy subjects was in the range of 40-60% of dose. Patients with acute hepatitis excreted only 10-20% of dose and patients with liver cirrhosis only about 5% of dose. In rats with "galactosamine hepatitis" hexobarbital clearance in vivo was distinctly reduced and this could be explained by diminished microsomal cytochrome p 45- and hexobarbital oxidation rate.
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The pharmacokinetics and relative bioavailability of cyclobarbital calcium have been studied after oral administration of Phanodorm, of tablets according to the Formularium Nederlandse Apothekers (1968; FNA), and an aqueous solution. Six healthy volunteers participated in the investigation on three occasions and each received the three preparations. The dose administered was 300 mg cyclobarbital calcium. Plasm concentrations of cyclobarbital were determined at regular intervals. Absorption from the three preparations was rapid was faster from the solution. Peak concentrations were usually attained within 1 h. The eleimination of cyclobarbital could be described by a single first-order process with an average half-life of 11.6 h (range 8 - 17 h). There was little intra-subject variation of the half-life. Relative bioavailability for each volunteer was estimated by comparing the areas under the plasma concentration curves. The RNA-tablets and Phanodorm exhibited similar bioavailability, whereas the average bioavailability of the solution was 78% of that of FNA-tablets; the reason for this unexpected finding is unknown. It was concluded that cyclobarbital cannot be regarded as a uniformly suitable drug for the treatment of insomnia. The long half-life that was apparent in some of the volunteers (15 - 17 h) creates a substantial risk of residual effects on the following morning. In principle, however, the calcium salt of cyclobarbital may be used for induction of sleep, because of its rapid absorption.
A sensitive method, using gas chromatography with nitrogen selective detection, has been developed for the accurate measurement of methohexitone, in plasma, in concentrations of less than 0.05 mug/ml, and which makes it possible to study the pharmacokinetics of the drug after clinical doses in man. Methohexitone sodium 3.0 mg/kg was administered by zero-order infusion to healthy volunteers and plasma concentrations were measured during and after infusion. The decrease in the plasma concentration of methohexitone can be described by two-compartment kinetics. The terminal elimination half-life of the drug is relatively short (70-125 min), which is a result of a high metabolic clearance rate (657-999 ml plasma/min). It was concluded that uptake of the drug by adipose tissue does not contribute significantly to its pharmacokinetics in man. In addition to the initial redistribution of an anaesthetic dose of methohexitone, the quick recovery of patients is a result of rapid metabolism of the drug.
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A sensitive and specific method for the quantitative determination of 5-vinyl-5-(1-methylbutyl)-barbituric acid (vinylbital) in plasma was developed, by using gas chromatography with alkali flame ionization detection. The method is suitable for measuring vinylbital plasma levels in man after administration of therapeutic doses. The pharmacokinetics and relative bioavailability of vinylbital after oral and rectal administration were studied in man. Tablets (Bykonox) containing 150 mg vinylbital, were used for the oral experiments and suppositories (Suppoptanox, polyethylene glycol base) containing 200 mg vinylbital, were used for rectal administration. Six volunteers participated in a cross-over way in the study. Vinylbital plasma concentrations were determined at regular intervals after drug administration. Absorption and elimination of vinylbital appeared to occur according to a single first-order process and the plasma concentrations were fitted by computer according to the equation intrinsic to the one-compartment open model after oral or rectal administration. The lag time was shorter for the suppository than for the tablet, whereas the absorption rate was faster for the tablet (mean absorption half-life 0.24 h compared with 0.64 h for the suppository). The elimination half-life of vinylbital varied from 17.6 to 33.5 h, with a mean value of 23.5 h for oral administration and 23.8 h for rectal administration. The half-lives were not considerably different on the two occasions for the individual volunteers. The average bioavailability of vinylbital for the suppository, relative to the tablet, was approximately 93%. Three volunteers collected their urine during 3--4 days after administration of a tablet. Unchanged vinylbital was determined and approximately 1.6% of the administered dose was excreted as unchanged drug. Some preliminary experiments of repetive vinylbital administration showed that self-induction of metabolism did not occur.
A method has been developed for the quantitative determination of heptabarbital [5-(1-cyclohepten-1-yl)-5-ethylbarbituric acid] in human plasma after administration of single therapeutic doses of the drug. It involves a single extraction step followed by gas chromatography with alkali flame ionization detection, and the results were linear in the concentration range 0.125 - 5.0 mug/ml plasma. The pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium were studied in a crossover design in 7 healthy volunteers after oral administration of 20 tablets containing 200 mg heptabarbital and hard gelatine capsules containing an equivalent amount of its sodium salt. Heptabarbital concentrations in plasma were determined at regular intervals. The absorption of heptabarbital from the tablets absorbed more rapidly and peak concentrations occurred between 1/3 and 2 h. In all cases the elimination of heptabarbital could be described by a single first-order process with an average half-life of 7.6 h (range 6.1 - 11.2 h). The half-life of the drug in each individual was about the same in the two trials. The relative bioavailability in each volunteer was estimated by comparing the areas under the plasma concentration curves. The sodium salt had an average bioavailability of 83% relative to the free acid. In some volunteers urinary excretion of unchanged heptabarbital was measured; cumulative excretion amounted to 0.16 - 0.30% of the administered dose. Four volunteers received one tablet each night for eight or ten days, but no accumulation was found. In three volunteers the half-life of the drug prior to and after these experiments did not change, whereas in the other volunteer the half-life decreased from 7.1 to 4.6 h. The possibility of enzyme induction should be considered when heptabarbital is taken regularly. It was concluded that heptabarbital was a suitable drug for the treatment of insomnia, since its half-life was rather short. Heptabarbital sodium may be used for induction of sleep, whereas Medomin tablets, i.e. heptabarbital free acid, may be prescribed when the maintenance of sleep is the primary reason for treatment with a hypnotic drug.
Five healthy volunteers took 1.2 g rifampicin daily for 8 days, and before and afterwards each received hexobarbital (7.32 mg/kg) and tolbutamide (20 mg/kg) by i.v. infusion on two consecutive days. The plasma concentrations of the two drugs were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 325 to 122 min and of tolbutamide from 418 to 183 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased about three-fold and that of tolbutamide more than two-fold. Significant changes in the distribution kinetics of the two drugs were not observed. The results suggest that rifampicin is capable of inducing drug metabolism in man, which leads to an increased rate of elimination of drugs that undergo biotransformation in the liver.
The pharmacokinetics of hexobarbital were studied in 13 patients with acute hepatitis. Hexobarbital sodium was administered by zero order intravenous (iv) infusion, and plasma concentrations were determined regularly by gas chromatography. For each patient the data were fitted according to 2-compartment kinetics. The results were compared to those obtained for 14 healthy volunteers. The elimination half-life of hexobarbital was 490 +/- 186 min in the hepatitis patients and 261 +/- 69 min in the control group. Clearance was significantly reduced in the hepatitis group, whereas the volume of distribution at steady state was not significantly altered. For some patients the initial distribution volume was reduced. In 6 patients the experiment with hexobarbital was repeated after apparent recovery from hepatitis as judged by normal transaminase and bilirubin levels. Generally the half-life of hexobarbital was shorter and the clearance value was higher than during the acute illness, but the values had not yet returned to normal. Clinical recovery from liver disease is not accompanied by corresponding recovery of drug-metabolizing capability.
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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).
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