Relationships of brain and plasma levels of quazepam, flurazepam, and their metabolites with pharmacological activity in mice

Hilbert, James; Iorio, Louis C.; Moritzen, Virginia; Barnett, Allen; Symchowicz, Samson; Zampaglione, Nicola

doi:10.1016/0024-3205(86)90451-0

Cited by 16 publications

(8 citation statements)

References 11 publications

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“…Despite the small number of data points, HPLC retention was highly correlated with brain uptake ratio (r = O.9O). ~O!1 Hurazepam is metabolized in mice to ETOH-FLZ and DA-FLZ (Hilbert et al 1986) similar to its pathway in other species including cats and humans (Eckert etal. 1983;Chiueh et al 1985).…”

Section: Relation Of Brain Uptake To Hplc Retentionmentioning

confidence: 99%

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites

et al. 1988

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The benzodiazepine derivative flurazepam (FLZ) is widely used as a hypnotic, but the relative contributions of FLZ and its metabolites desalkylflurazepam (DA-FLZ), hydroxyethylflurazepam (ETOH-FLZ), and flurazepam aldehyde (CHO-FLZ) to overall clinical activity remain uncertain. A single 20 mg/kg dose of FLZ.HCl was administered to mice, with plasma and brain concentrations of FLZ and metabolites determined during 5 h after dosage. Brain and plasma concentrations of FLZ were maximal at 0.5 h after dosage, then declined rapidly in parallel, whereas those of DAFLZ were maximal at 2 h, then declined slowly. Concentrations of ETOH-FLZ, the most polar metabolite, were maximal at 0.5 h, and were undetectable after 3 h. Little CHO-FLZ was detected in either brain or plasma. A single 30-mg oral dose of FLZ.HCl was given to 18 human volunteers, with plasma levels determined over 9 days. FLZ was detected in plasma at low concentrations for no more than 3 h after dosage. ETOH-FLZ concentrations were higher and persisted for 8 h after dosage. CHO-FLZ reached intermediate peak levels and was present longer than FLZ or ETOH-FLZ. In contrast, DA-FLZ achieved the greatest peak concentrations, occurring at 10 h after dosage. Levels declined very slowly, with a mean half-life of 71.4 h, and were still detectable 9 days after FLZ dosage. Plasma free fractions (percent unbound) in mice were 40.3, 51.4, and 25.0% for FLZ, ETOH-FLZ and DA-FLZ, respectively; in humans, values were 17.2, 35.2, and 3.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Relation Of Brain Uptake To Hplc Retentionmentioning

confidence: 99%

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites

et al. 1988

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“…Documentation of the CSF uptake ki netics of desalkylflurazepam in this experi mental model would require administration either of considerably higher doses of fluraz epam itself, or administration of desalkyl flurazepam in its pure form. It is important to note that entry of desalkylflurazepam into brain tissue has been clearly documented in other experimental models [21,23,24], The nondetection of flurazepam and desalkylflurazepam in brain tissue in the present study likewise is probably because levels present at the completion of the 8-hour study were below the limits of assay detection.…”

Section: Discussionmentioning

confidence: 57%

Pharmacokinetics and CSF Entry of Flurazepam in Dogs

et al. 1988

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Anesthetized dogs received a single 1.0-mg/kg intravenous dose of flurazepam hydrochloride, following which multiple blood and cerebrospinal fluid (CSF) samples were taken over the next 8 h. Concentrations of flurazepam and its metabolite, desalkylflurazepam, were determined by gas chromatography with electron-capture detection. Mean kinetic variables for flurazepam were: volume of distribution 7.9 1/kg, elimination half-life 2.3 h, clearance 37 ml/min/kg, serum free fraction 25% unbound. The metabolic product desalkylflurazepam appeared in serum in low concentrations, and was eliminated with a half-life of 4.9 h. Flurazepam rapidly entered CSF, then was eliminated in parallel with flurazepam in serum. However, the extent of entry into CSF was limited, with the mean ratio of area under the curve for CSF versus serum (0.24) nearly identical to the serum free fraction. Thus, intravenous flurazepam in dogs is characterized by extensive distribution, high clearance, and short half-life. Entry into CSF is rapid, and appears governed by passive diffusion. The extent of CSF entry is limited by protein binding in serum.

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“…There has been no study showing the relation of plasma quazepam concentrations to its hypnotic effects. However, the brain level of quazepam was reported to parallel the plasma level [17]. We can say that no sedation occurred on the next morning with quazepam 45 mg when the plasma quazepam concentration was 30 to 65 ng·ml −1 .…”

Section: Discussionmentioning

confidence: 95%

“…In the present study, no patients were drowsy with an M6 concentration higher than 40 ng·ml −1 . In the presence of quazepam and M4, M6 is reported not to contribute extensively to the observed pharmacological activity [17].…”

Section: Discussionmentioning

confidence: 99%

Effects of quazepam as a preoperative night hypnotic: comparison with brotizolam

et al. 2007

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Relationships of brain and plasma levels of quazepam, flurazepam, and their metabolites with pharmacological activity in mice

Cited by 16 publications

References 11 publications

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites

Pharmacokinetics and CSF Entry of Flurazepam in Dogs

Effects of quazepam as a preoperative night hypnotic: comparison with brotizolam

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