Pharmacokinetics of 4-Hydroxybutyric Acid in Man, Rhesus Monkey and Dog

Vree, T. B.; Damsma, J. E.; Bogert, A. G. van den; Kleijn, Eppo van der

doi:10.1007/978-3-642-66925-5_3

Cited by 17 publications

(16 citation statements)

References 13 publications

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“…injection of 1,4-butanediol in humans, the plasma concentration time profile of γ-hydroxybutyric acid as metabolite is nearly superimposable over that obtained after i.v. injection of γ-hydroxybutyric acid as parent (Vree et al, 1978). Current evidence is consistent with 1,4-butanediol first being oxidized to γ-hydroxy-butyraldehyde by alcohol dehydrogenase, and then the intermediate aldehyde oxidized by aldehyde dehydrogenase (ALDH) to γ-hydroxybutyrate.…”

Section: 4-butanediol Metabolismmentioning

confidence: 69%

“…However, after parenteral administration the pharmacologic action of γ-butyrolactone is essentially identical to that of 1,4-butanediol and γ-hydroxybutyric acid (Giarman and Roth, 1964;Sprince et al, 1966;Snead, 1992) due to its conversion to γ-hydroxybutyric acid in liver. The cyclic lactone is less polar than the acid and therefore absorbed much more rapidly after oral administration, however, conversion to the acid is so rapid after absorption that γ-hydroxybutyric acid bioavailability is actually greater after administration of γ-butyrolactone than after administration of an equivalent dose of Na-γ-hydroxybutyric acid (Vree et al, 1978;Lettieri and Fung, 1978). Because of the rapid conversion to γ-hydroxybutyric acid after absorption of γ-butyrolactone, it is frequently used as a prodrug for γ-hydroxybutyric acid.…”

Section: Pharmacologymentioning

confidence: 96%

“…The major biotransformation route in brain, liver, kidney and heart, is oxidation to γ-hydroxybutyric acid (Roth andGiarman, 1966, 1968;Maxwell and Roth, 1972;Vree et al, 1978;Snead et al, 1989). This conversion occurs very rapidly; following i.v.…”

Section: 4-butanediol Metabolismmentioning

confidence: 97%

“…Partial hepatectomy caused a significant reduction in the formation of 14 C-γ-hydroxybutyric acid derived from 14 C-1,4-butanediol and also reduced the length of 1,4-butanediol induced sleeping time, indicating that the liver is the major site where exogenously administered butanediol is converted to γ-hydroxybutyric acid. Vree et al (1978) followed the concentration of γ-hydroxybutyric acid in the blood of dogs, monkeys or humans after i.v. injection of γ-hydroxybutyric acid, γ-hydroxybutyric acid-ethyl ester, or 1,4-butanediol.…”

Section: Pharmacologymentioning

confidence: 99%

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A review of evidence leading to the prediction that 1,4-butanediol is not a carcinogen

Irwin

2005

J. Appl. Toxicol.

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1,4-Butanediol is an industrial chemical used primarily as an intermediate in the manufacture of other organic chemicals. It has recently been associated with deaths, addiction and withdrawal related to its promotion and use as a dietary supplement. The rapid absorption and conversion of 1,4-butanediol to gamma-hydroxybutyric acid (GHB, or date rape drug) in animals and humans is well documented and is the basis for its abuse potential. A disposition and metabolism study conducted in F344 rats by the National Toxicology Program (NTP) confirmed the rapid conversion of 1-(14)C-1,4-butanediol to (14)CO2. Because of this, the toxicological profile of 1,4-butanediol resembles that of gamma-hydroxybutyric acid. Gamma-hydroxybutyric acid occurs naturally in the brain and peripheral tissues and is converted to succinate and metabolized through the TCA cycle. Although the function of gamma-hydroxybutyric acid in peripheral tissues is not known, the presence of specific high affinity receptors for gamma-hydroxybutyric acid suggests that it functions as a neuromodulator in the brain and neuronal tissue. Gamma-hydroxybutyric acid readily crosses the blood-brain barrier and elicits characteristic neuropharmacologic responses after oral, i.p., or i.v. administration. The same responses are observed after administration of 1,4-butanediol. The cyclic lactone of gamma-hydroxybutyric acid, gamma-butyrolactone, is also rapidly converted to gamma-hydroxybutyric acid by enzymes in the blood and liver in animals and humans, and produces pharmacological effects identical to those produced by 1,4-butanediol and gamma-hydroxybutyric acid. Gamma-butyrolactone was previously evaluated by the NTP in 14-day and 13-week prechronic toxicology studies and in 2-year chronic toxicology and carcinogenesis studies in F344 rats and B6C3F1 mice. No organ specific toxicity occurred. In the carcinogenesis studies there was an equivocal response in male mice based on a marginal increase in the incidence of pheochromocytomas of the adrenal medulla. Because the absence of chronic toxicity and significant carcinogenicity of gamma-hydroxybutyric acid were established in NTP prechronic and chronic studies with gamma-butyrolactone, it is concluded that similar results would be obtained in a 2-year study with 1,4-butanediol, and that 1,4-butanediol is not a carcinogen.

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Section: 4-butanediol Metabolismmentioning

confidence: 69%

Section: Pharmacologymentioning

confidence: 96%

Section: 4-butanediol Metabolismmentioning

confidence: 97%

Section: Pharmacologymentioning

confidence: 99%

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A review of evidence leading to the prediction that 1,4-butanediol is not a carcinogen

Irwin

2005

J. Appl. Toxicol.

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“…Literature reports have indicated that 1 ,rl-butanediol possesses sedative activity in man, due to its rapid metabolism by alcoholdehydrogenase to 4-hydroxybutyric acid, which is a very useful sedative in intensive care units. [16][17][18] The combination of VPA and 1 ,Cbutanediol may lead to synergistic activity.…”

Section: S Hadad Et a Lmentioning

confidence: 98%

Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid

Hadad

Vree

Kleijn

et al. 1993

Biopharm & Drug Disp

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The pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4-butanediol divalproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4-butanediol.

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Intravenöse Hypnotika und Anästhetika

Sonntag¹

1992

Anästhesiologie

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Pharmacokinetics of 4-Hydroxybutyric Acid in Man, Rhesus Monkey and Dog

Cited by 17 publications

References 13 publications

A review of evidence leading to the prediction that 1,4-butanediol is not a carcinogen

A review of evidence leading to the prediction that 1,4-butanediol is not a carcinogen

Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid

Intravenöse Hypnotika und Anästhetika

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