Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man

Klotz, Ulrich; Ziegler, G.; Reimann, I. W.

doi:10.1007/bf00553165

Cited by 20 publications

(26 citation statements)

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“…Flumazenil is extensively metabolized in the liver (18,19). The proposed metabolic pathways of flumazenil lead to formation of a free acid (Ro 15-3890), alcohol (Ro 15-4965) and desmethyl (Ro 15-5528) compounds after hydrolysis and oxidation respectively (20).…”

Section: Methodsmentioning

confidence: 99%

Plasma pharmacokinetics and metabolism of the benzodiazepine antagonist [11C] Ro 15-1788 (flumazenil) in baboon and human during positron emission tomography studies

Debruyne

Abadie

Barré

et al. 1991

European Journal of Drug Metabolism and Pharmacokinetics

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Flumazenil is a specific antagonist of the central benzodiazepine receptor (CBZR). Labelled with 11C, this compound is the reference radioligand for positron emission tomography (PET) study of the CBZR in humans and primates. The time-course of [11C]-flumazenil radioactivity and its main acid metabolite [11C] Ro 15-3890 were reconstructed from the time-course of total radioactivity in plasma after administration with high or low SRA in primates and humans, applying an extraction procedure validated by TLC. The measured pharmacokinetics of [11C]-flumazenil (T1/2 beta = 45.1 +/- 12.3 min, T1/2 alpha = 1.5 +/- 1.5 min; K = 0.14 +/- 0.14 min-1; Vd area = 44.0 +/- 17.0 l; Clp = 40.0 +/- 8.5 l/h) exhibited a very rapid distribution phase followed by fast elimination, with a large volume of distribution; these results were confirmed by HPLC determinations and agree with previously published data on unlabelled flumazenil. Pharmacokinetics of [11C] Ro 15-3890 acid metabolite show that high drug concentrations in the blood are promptly achieved (kf = 0.13 +/- 0.004 min-1), with a very rapid elimination half-life (T1/2m = 4.47 +/- 1.31 min) comparable to that of [11C]-flumazenil. The percentage metabolization of parent compound to the acid [11C] Ro 15-3890 was constant from the 15th minute and was significantly higher in man compared to the monkey. This percentage was increased by prior eating. The other putative metabolites, i.e. labelled [11C] Ro 15-4965 and unlabelled Ro 15-5528, were never observed at detectable concentrations with TLC and HPLC in rabbit, baboon and human blood samples. This pharmacokinetic study of plasma flumazenil may be useful to implement a dynamic method of CBZR quantification using PET and for analysis of pharmacokinetics in brain tissue.

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Section: Methodsmentioning

confidence: 99%

Plasma pharmacokinetics and metabolism of the benzodiazepine antagonist [11C] Ro 15-1788 (flumazenil) in baboon and human during positron emission tomography studies

Debruyne

Abadie

Barré

et al. 1991

European Journal of Drug Metabolism and Pharmacokinetics

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“…This effect was only visible by regarding the time period of 60 min after injection, when Ro 15-1788 is detectable in plasma, as can be derived from our kinetic data (Klotz et al, 1984), or over shorter periods (30 min).…”

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 98%

“…In the first clinical trials it was found that this drug could reverse the sedative-hypnotic effects of clonazepam, diazepam, flunitrazepam, midazolam, and other benzodiazepines rapidly ( see Hunkeler et al, 1981;Bonetti et al, 1982;Klotz et al, 1985). The very short duration of action corresponds weil to the elimination half-life time of about 0.97 ± 0.2 hours (Klotz et al, 1984).Most studies for evaluating the possible intrinsic effects of Ro 15-1788 were done in waking probands and showed no behavioral or physiological effects (Polc et al, 1981; Darragh et al, 1983 b) even up to very high doses of 600 mg. In contrast, Schöpf et al (1984) could demonstrate a slight central stimulation after a single iv-dose of 5 mg in normal waking subjects.…”

mentioning

confidence: 96%

“…The very short duration of action corresponds weil to the elimination half-life time of about 0.97 ± 0.2 hours (Klotz et al, 1984).…”

mentioning

confidence: 99%

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Effect of the Specific Benzodiazepine Antagonist Ro 15-1788 on Sleep

Ziegler¹,

Ludwig²,

Fritz³

1986

Pharmacopsychiatry

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In troductionThe selective antagonistic efficacy of the benzodiazepine antagonist Ro 15-1788 is weil established. In the first clinical trials it was found that this drug could reverse the sedative-hypnotic effects of clonazepam, diazepam, flunitrazepam, midazolam, and other benzodiazepines rapidly ( see Hunkeler et al., 1981;Bonetti et al., 1982;Klotz et al., 1985). The very short duration of action corresponds weil to the elimination half-life time of about 0.97 ± 0.2 hours (Klotz et al., 1984).Most studies for evaluating the possible intrinsic effects of Ro 15-1788 were done in waking probands and showed no behavioral or physiological effects (Polc et al., 1981; Darragh et al., 1983 b) even up to very high doses of 600 mg. In contrast, Schöpf et al. (1984) could demonstrate a slight central stimulation after a single iv-dose of 5 mg in normal waking subjects. Some preliminary clinical data indicate an anticonvulsant effect (Scollo-Lavizzari, 1984) and possibly clinical improvement in hepatic encephalopathy (Bansky et al., 1985), both accociated with a modulation of GABAergic activity.In an own study (Klotz et al., 1985), we demonstrated an imperative awakening of the subjects after an iv-bolus of 2.5 mg of Ro 15··1788 from slow-wave-sleep induced by infusion with Midazolam. It is well known that benzodiazepines (BZD) act on GABAergic system by amplifying the GABAtransmission in the CNS. Since the GABAergic system is also involved in sleep regulation, we studied the intrinsic effect of a single dose of 10 mg Ro 15-1788 on sleep in normal subjects without premedication of any drug. MethodsThe study was carried out in a sleep-laboratory in a double-blind cross-over design with 7 healthy volunteers (5 male, : female, aged 22-29 years, mean 24.5 ± 2.2). The subjects were free of any drugs and had no difficulties in sleep habits. They were all screened by a physical and psychological test and fully informed about the study, their written consent was given.After one adaptation night with EEG-recording, either 10 mg Ro 15-1788 or identical Placebo was given in a randomized order as a bolus intravenously via an infusion tube with smaU volume from outside the room without awakening the probands.Injection was done while the first slow wave sleep epochs (stable over > 3 min) triggered by EEG, which was monitored continously and recorded according to the standardized rules by Rechtschaffen & KaIes (1968). Injection times were not different between the conditions. Sieep records were analyzed by a well trained rater without knowledge of injection times and drug condition by visual rating in 30-sec epochs over the whole night and for the 60 min after injection, in accord with the short duration of action of Ro 15-1788.Sieep parameters were computed by a software package (SLAP) and statistically analyzed by the t-test and parameter-free (Wilcoxon-test) if data were not normally distributed. Additionally. all subjects were asked each morning about sleep-q uahty using visual analogue scales. ResultsAs can be seen from Table 1...

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Parametric in vivo imaging of benzodiazepine receptor distribution in human brain

Frey

Holthoff-Detto²,

Koeppe

et al. 1991

Annals of Neurology

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Emission computed tomographic methods for the in vivo quantification of radioligand-binding sites in human brain have previously been limited either by a lack of correction for possible effects of altered ligand transport or by highly complicated physiological models that preclude display of binding data in a detailed anatomical format. We investigated the application of a simplified compartmental model to the kinetic analysis of in vivo ligand binding to central benzodiazepine receptors. The human brain distribution of [11C]flumazenil, as determined by dynamic positron emission tomography, combined with metabolite-corrected arterial blood samples, permitted estimations of local cerebral ligand transport and of receptor binding. This approach allows calculation of transport and binding "maps" on a pixel-by-pixel basis, resulting in the display of binding data in a familiar tomographic format while maintaining much of the physiological accuracy inherent in more complex methods. The results obtained in a study of 6 normal volunteers revealed good interindividual precision, with coefficients of variation between 10 and 15% of mean regional values, suggesting the utility of this approach in future clinical studies of benzodiazepine receptor binding.

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Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man

Cited by 20 publications

References 25 publications

Plasma pharmacokinetics and metabolism of the benzodiazepine antagonist [11C] Ro 15-1788 (flumazenil) in baboon and human during positron emission tomography studies

Plasma pharmacokinetics and metabolism of the benzodiazepine antagonist [11C] Ro 15-1788 (flumazenil) in baboon and human during positron emission tomography studies

Effect of the Specific Benzodiazepine Antagonist Ro 15-1788 on Sleep

Parametric in vivo imaging of benzodiazepine receptor distribution in human brain

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