Metabolic Fate of Hexobarbital (HBj

Bush, Milton T.; Weller, William L.

doi:10.3109/03602537208993914

Cited by 51 publications

(10 citation statements)

References 37 publications

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“…Hexobarbital is completely metabolized in the li v er. 10 The almost threefold increase in drug c1earance indicates substantial induction by rifampicin. Within a fortnight this effect disappeared and c1earance returned to control values (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Blood sampIes (5 ml) were generally taken at 1, 2,4,6,8,10,12,16,20, and 24 hr following drug infusion.…”

Section: Methodsmentioning

confidence: 99%

“…On day 2 galactose (0.30 gm/kg) was administered by linear intravenous infusion (5 min). Blood sampies (2 ml) were taken after 10,20,25,30,35,40,45,50, and 60 min. Urine was collected for 4 hr following drug infusion.…”

Section: Methodsmentioning

confidence: 99%

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Influence of rifampicin on drug metabolism: Differences between hexobarbital and antipyrine

Breimer

Zilly

Richter

1977

Clin Pharma and Therapeutics

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Six healthy volunteers were treated with 1,200 mg of rifampicin daily for 8 days. Before and immediately afterward each received indocyanine green, hexobarbital, galactose, and antipyrine by intravenous infusion on 3 consecutive days. The plasma concentrations of the drugs were determined several times after infusion. The average elimination half-life of hexobarbital had decreased from 407 to 171 min and its metabolic clearance had increased almost threefold. In contrast, the average elimination half-life of antipyrine was virtually the same on both occasions (6.9 and 7.2 hr) and there was no change in metabolic clearance. In a tuberculous patient treated with rifampicin the antipyrine elimination rate was unaffected. Rifampicin did not influence indocyanine green clearance or galactose elimination capacity. Serum gamma glutamyl transferase was not affected but urinary D-glucaric acid excretion was increased during rifampicin treatment. The experiment with hexobarbital was repeated after 2 weeks in all subjects; half-lives and clearance values had returned to near control values. It appears that rifampicin is a selective inducer of oxidative drug metabolism in man.

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Section: Discussionmentioning

confidence: 99%

“…Blood sampIes (5 ml) were generally taken at 1, 2,4,6,8,10,12,16,20, and 24 hr following drug infusion.…”

Section: Methodsmentioning

confidence: 99%

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Influence of rifampicin on drug metabolism: Differences between hexobarbital and antipyrine

Breimer

Zilly

Richter

1977

Clin Pharma and Therapeutics

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“…The metabolism of hexobarbitone is, however, rather complicated. It is thought to be initiated predominantly by hepatic 0306-5251/83/0400-4590 $02.00 mono-oxygenase reactions, such as allylic side-chain oxidation which leads to 3'-hydroxy-and 3'ketohexobarbitone (Bush & Weller, 1972) and to epoxidation of the 1',2'-olefinic bond, which leads, via an epoxide-diol pathway, to the formation of 1,5-dimethylbarbituric acid (Vermeulen et al, 1978.…”

Section: Introductionmentioning

confidence: 99%

Disposition of hexobarbitone in healthy man: kinetics of parent drug and metabolites following oral administration.

Vermeulen

Rietveld²,

Breimer³

1983

Brit J Clinical Pharma

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1 Hexobarbitone plasma kinetics were determined in six healthy volunteers, who received 500 mg hexobarbitone orally. In addition urinary excretion rate and cumulative excretion were measured of its three major metabolites: 3'-hydroxyhexobarbitone, 3'-ketohexobarbitone and 1,5-dimethylbarbituric acid. 2 The mean plasma elimination half-life of hexobarbitone was 3.7 + 0.9 h (n = 6). Assuming complete absorption, the volume of distribution and the metabolic clearance were 81.3 + 20.5 1 and 16.4 + 2.9 1/h, respectively. The mean maximal plasma concentration was 7.1 + 2.1 ,ug/ml and was reached 1.2 + 0.4 h after drug administration. 3 3'-Hydroxyhexobarbitone and 3'-ketohexobarbitone, which are products of allylic side-chain oxidation of hexobarbitone, were excreted in 24 h to the extent of 4.7 + 1.3 and 32.1 + 11.9% of the dose, respectively. In the same period, 1,5-dimethylbarbituric acid, which is the end product of the epoxide-diol pathway, was excreted to 18.0 + 7.8% of the dose. The ratio of the sum of 3'-hydroxyand 3'-ketohexobarbitone vs 1,5-dimethylbarbituric acid excreted varied with time and amounted ultimately in 24 h urine to 2.3 + 1.0. 4 The half-lives of 3'-hydroxyhexobarbitone and 1,5-dimethylbarbituric acid, calculated from their renal excretion rate curves, amounted 5.2 + 0.9 and 6.6 + 1.3 h and were significantly longer than the half-life of hexobarbitone in plasma. The half-life of 3'-ketohexobarbitone was 4.2 + 0.8 h. The maximum excretion rate of 1 ,5-dimethylbarbituric acid was reached at 7.7 + 1.0 h after administration of hexobarbitone. 3'-Hydroxy-and 3'-ketohexobarbitone were excreted with a maximal rate at 2.2 ± 0.8 and 2.8 + 0.4 h respectively.

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“…Many efforts have been made to acquire quantitative information on this capacity by measuring the in vivo pa rameters of endogenous compounds or the rates of elimination from plasma of exoge nous compounds [Vesell, 1979;Danhof, 1980;Breimer et al, 1983], One of the widely used model drugs in the assessment of hepatic drug metabolizing activity in ani mals and also in man is hexobarbital [Bush and Weller, 1972;Holcomb et al, 1974], Hexobarbital is completely metabolized in the liver via the mixed function mono-oxy genase system and it is generally believed that the duration of its hypnotic action is a reasonable reflection of its overall rate of metabolism [Bush and Weller, 1972], Recently, however, hexobarbital was shown to undergo first-pass elimination in the rat to an extent of about 70% after oral application. Under such conditions the sys temic clearance, as estimated upon intrave nous administration, is affected by liver blood flow as well as by the metabolizing enzyme activity of the liver [Gibaldi and Perrier, 1974;Wilkinson and Shand, 1975], In order to estimate the intrinsic hepatic clearance, merely reflecting the metabolizing capacity, the oral route of administration should be applied [Vermeulen, 1980], Doses of 50-100 mg/kg as usually administered in previous rat experiments [Holcomb et al, 1974;Breimer and van Rossum, 1974;Drew et al, 1977;Richter et.…”

Section: Introductionmentioning

confidence: 99%

Influence of the Rate of Hepatic Portal Vein Infusion on Hexobarbital Pharmacokinetics in the Rat

1988

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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 μg·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 μg·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.

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Metabolic Fate of Hexobarbital (HBj

Cited by 51 publications

References 37 publications

Influence of rifampicin on drug metabolism: Differences between hexobarbital and antipyrine

Influence of rifampicin on drug metabolism: Differences between hexobarbital and antipyrine

Disposition of hexobarbitone in healthy man: kinetics of parent drug and metabolites following oral administration.

Influence of the Rate of Hepatic Portal Vein Infusion on Hexobarbital Pharmacokinetics in the Rat

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