Highly sensitive assay of a benzodiazepine antagonist in plasma by capillary gas chromatography with nitrogen-selective detection

Zell, Manfred; Timm, U.

doi:10.1016/s0378-4347(00)83515-x

Cited by 28 publications

(7 citation statements)

References 19 publications

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“…However, a recent publication (Zell and Timm, 1986) gives a half-life of 43 minutes for one subject after an intravenous dose of 2 mg of the drug. A review on the pharmacokinetics of Ro 15-1788 is given by Klotz and Kanto (1988).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of the benzodiazepine antagonist ¹¹C‐Ro 15‐1788 after intravenous administration in man

Swahn

Persson

Pauli

1989

Human Psychopharmacology

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The metabolic fate of the benzodiazepine antagonist RO 15-1788 labelled with "C was studied in plasma from human subjects after intravenous administration in connection with positron emission tomography. R o 15-1788 and its metabolites were separated by thin-layer chromatography and the radioactivity in the different compounds was determined. "C-Ro 15-1788 was extensively and rapidly metabolised to the corresponding free acid. At 36 minutes after administration only 50% of the radioactivity in plasma represented unchanged compound.

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Section: Discussionmentioning

confidence: 99%

Metabolism of the benzodiazepine antagonist ¹¹C‐Ro 15‐1788 after intravenous administration in man

Swahn

Persson

Pauli

1989

Human Psychopharmacology

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“…2) [Ndesmethylflumazenil, N-desmethylflumazenil 'acid' and flumazenil 'acid'] have been identified (G. Wendt, unpublished data cited by Zell & Timm 1986). However, no further information is currently available.…”

Section: Metabolismmentioning

confidence: 99%

Pharmacokinetics and Clinical Use of Flumazenil (Ro 15-1788)

Klotz

Kanto

1988

Clinical Pharmacokinetics

122

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Flumazenil (Ro 15-1788) is a specific benzodiazepine antagonist which can prevent or abolish selectively at the receptor level all centrally mediated effects of benzodiazepines. Following oral administration flumazenil is rapidly absorbed (peak concentrations are achieved after 20 to 90 minutes), but bioavailability is low (16%) due to significant presystemic elimination. As less than 0.2% of an intravenous dose was recovered as unchanged drug in the urine, extensive metabolism must occur and so far 3 metabolites of flumazenil (N-demethylated and/or hydrolysed products) have been identified. For the clinical value of flumazenil a rapid onset of action is mandatory, which is facilitated by its fast uptake and regional brain distribution as verified by positron emission tomography. The limited duration of benzodiazepine-antagonistic action of flumazenil (2 to 3 hours) is due to its rapid hepatic elimination. This can be characterised either by the short half-life (0.7 to 1.3 hours) or better by the high plasma or blood clearance of 520 to 1300 ml/min (31 to 78 L/h). The low plasma protein binding of flumazenil (about 40%) will not limit its wide distribution (apparent distribution volume 0.6 to 1.6 L/kg) or its partly flow-dependent hepatic elimination. Whereas in first trials flumazenil appeared to be without its own pharmacological effects, there is now increasing evidence that flumazenil is not devoid of intrinsic actions. Dependent on the dose, the basal clinical conditions and experimental tests, flumazenil has both weak agonist-like and inverse agonist-like properties which might be explained by a modulation of GABA-ergic activity. In several clinical studies intravenous doses down to 0.2mg of flumazenil initiated a rapid and reliable reversal of benzodiazepine-induced sedation, hypnosis or coma. Small incremental intravenous doses of 0.1 to 0.2mg of flumazenil are useful in benzodiazepine intoxications, in differential diagnosis of coma, excessive postoperative sedation and possibly in reversing paradoxical reactions of benzodiazepines. Because flumazenil is short acting, careful clinical observation is crucial. To maintain its antagonistic action repeated administrations will be necessary. At present, the therapeutic indications are restricted to some special situations. However, flumazenil is an interesting agent, which might contribute also to a better understanding and future development of more specific benzodiazepines, hopefully without the potential for dependence seen with existing compounds.

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“…The blood was separated by centrifugation and the supernatant plasma stored at -20°C until analysis by gas chromatography [8]. The limit of quantification for this analytical method was 100 pg.ml-' and the reproducibility was 4.56 to 6.07%.…”

Section: Methodsmentioning

confidence: 99%

Plasma concentrations of flumazenil during liver transplantation

Park

Podkowik

1992

Anaesthesia

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SummarySix patients were given Jlumazenil ( I mg) during the anhepatic period of liver transplantation. We found higher mean plasma Jlumazenil concentrations during the anhepatic period than occurred in patients with hepatic cirrhosis. It was only possible to measure plasma Jlumazenil concentrations in four patients after revascularisation of the donor liver. Of these, elimination halflives could be calculated in only three patients (normal in one and prolonged in two). In these two patients the elimination halflives were prolonged to the same extent as in patients with fulminant hepatic failure. The changes during the anhepatic period occur because the liver contributes to the central volume of distribution. After revascularisation of the donor organ the prolonged half-lives indicate that transplanted livers may not recover normal metabolic functions immediately.

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Highly sensitive assay of a benzodiazepine antagonist in plasma by capillary gas chromatography with nitrogen-selective detection

Cited by 28 publications

References 19 publications

Metabolism of the benzodiazepine antagonist ¹¹C‐Ro 15‐1788 after intravenous administration in man

Metabolism of the benzodiazepine antagonist ¹¹C‐Ro 15‐1788 after intravenous administration in man

Pharmacokinetics and Clinical Use of Flumazenil (Ro 15-1788)

Plasma concentrations of flumazenil during liver transplantation

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Highly sensitive assay of a benzodiazepine antagonist in plasma by capillary gas chromatography with nitrogen-selective detection

Cited by 28 publications

References 19 publications

Metabolism of the benzodiazepine antagonist 11C‐Ro 15‐1788 after intravenous administration in man

Metabolism of the benzodiazepine antagonist 11C‐Ro 15‐1788 after intravenous administration in man

Pharmacokinetics and Clinical Use of Flumazenil (Ro 15-1788)

Plasma concentrations of flumazenil during liver transplantation

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Metabolism of the benzodiazepine antagonist ¹¹C‐Ro 15‐1788 after intravenous administration in man

Metabolism of the benzodiazepine antagonist ¹¹C‐Ro 15‐1788 after intravenous administration in man