Entry of diazepam and its major metabolite into cerebrospinal fluid

Greenblatt, David J.; Ochs, Hermann R.; Lloyd, Brian L.

doi:10.1007/bf00432376

Cited by 91 publications

(22 citation statements)

References 20 publications

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“…Because of the unique characteristics of the brain capillary endothelium, the translocation of drugs and certain hormones across the blood-brain barrier has been considered a classic example of such transport (21). In the case of diazepam, the similarity of cerebrospinal fluid concentrations to those ofestimated unbound drug in systemic plasma is consistent with this conventional concept (22)(23)(24). However, data based on measurement of diazepam's unidirectional brain extraction by the tissue sampling, single carotid artery injection technique could not be explained on this basis.…”

Section: Discussionsupporting

confidence: 66%

Plasma binding and transport of diazepam across the blood-brain barrier. No evidence for in vivo enhanced dissociation.

Dubey¹,

McAllister²,

Inoue³

et al. 1989

J. Clin. Invest.

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The tissue uptake of extensively plasma-bound compounds is reportedly inconsistent with the conventional free-drug hypothesis limiting transport to unbound moiety in rapid intracapillary equilibrium with bound complex. Instead, proteinmediated/cell surface enhancement of dissociation has been postulated to occur in the microvasculature. This possibility was investigated by studying the passive transport of diazepam across the blood-brain barrier. Microdialysis probes placed within the vena cava and brain cortex were used to directly compare steady-state, interstitial unbound diazepam levels in both Wistar and genetically analbuminemic rats. The absence of albumin in the latter increased the unbound fraction of diazepam by almost fivefold; however, in both groups, the ratio of unbound concentrations in brain and blood at equilibrium was equal to unity. If enhanced dissociation occurred in the microvasculature, then the unbound brain level should have been greater than that in the systemic circulation. It is probable that earlier findings suggestive of protein-mediated transport reflect a nonequilibrium phenomenon. Comparison of the extent of diazepam's in vivo binding in blood by microdialysis to that estimated in vitro using conventional equilibrium dialysis with microcells showed good agreement, thus validating a widely accepted assumption of equivalency of these two values.

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Section: Discussionsupporting

confidence: 66%

Plasma binding and transport of diazepam across the blood-brain barrier. No evidence for in vivo enhanced dissociation.

Dubey¹,

McAllister²,

Inoue³

et al. 1989

J. Clin. Invest.

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“…As with previous studies of diazepam in the same species [12], flurazepam had high metabolic clearance averaging 37 ml/min/kg, and a short elimination half-life of 2.3 h. Like other lipophilic compounds [11], flura zepam was extensively distributed, with a mean volume of distribution of almost 8 1/kg. The only metabolite of flurazepam detected in serum was desalkylflurazepam, also a principal metabolite of flurazepam in humans [1,2,20,21], Other identified metabolic products of flurazepam were not measured in dog serum.…”

Section: Discussionmentioning

confidence: 52%

“…This experimental model has been utilized in previous studies to eval uate the serum pharmacokinetics, as well as the rate and extent of CSF entry, of a num ber of drug classes including benzodiaze pines, tricyclic antidepressants, neuroleptics, analgesics and antiarrhythmics [11][12][13], It is possible that the use of general anesthesia, which is necessary to allow cannulation of the CSF and repeated sampling from this site, could have altered the metabolic clear ance of the compounds evaluated in this and previous studies [ 13]. However, it is unlikely that anesthesia influenced peripheral tissue distribution and CSF entry, since these pro cesses appear to be governed by passive dis tribution.…”

Section: Discussionmentioning

confidence: 99%

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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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“…Concentrations of diazepam and its major metabolite, desmethyldiazepam, in each sample were determined by gas chromatography with electron capture detection (Greenblatt et al, 1980). All samples from a given subject's pair of trials were extracted and analyzed on the same day using the same calibration standards.…”

Section: Diazepam Studymentioning

confidence: 99%

Interaction of propoxyphene with diazepam, alprazolam and lorazepam.

Abernethy¹,

Dj²,

Morse³

et al. 1985

Brit J Clinical Pharma

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Healthy volunteers received single doses of three benzodiazepines (diazepam, 10 mg i.v.; alprazolam, 1.0 mg orally; lorazepam, 2 mg i.v.) on two occasions in random sequence. One trial was a control; for the other, subjects ingested propoxyphene, 65 mg every 6 h, for the duration of the benzodiazepine study. The kinetics of each benzodiazepine were determined from multiple plasma concentrations measured following each dose. For diazepam, propoxyphene produced a small and statistically insignificant prolongation of elimination half‐ life (43 vs 38 h) and reduction of total clearance (0.41 vs 0.47 ml min‐ 1 kg‐1). Propoxyphene significantly prolonged alprazolam half‐life (18 vs 12 h, P less than 0.005) and reduced total clearance (0.8 vs 1.3 ml min‐1 kg‐1, P less than 0.005). Propoxyphene had no apparent influence on lorazepam half‐life (13.4 vs 13.5 h) or clearance (1.5 vs 1.4 ml min‐ 1 kg‐1). Thus propoxyphene significantly impairs the clearance of alprazolam, biotransformed mainly by the oxidative reaction of aliphatic hydroxylation. Propoxyphene has far less effect on the oxidation of diazepam by N‐demethylation, and has no apparent influence on lorazepam conjugation.

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Entry of diazepam and its major metabolite into cerebrospinal fluid

Cited by 91 publications

References 20 publications

Plasma binding and transport of diazepam across the blood-brain barrier. No evidence for in vivo enhanced dissociation.

Plasma binding and transport of diazepam across the blood-brain barrier. No evidence for in vivo enhanced dissociation.

Pharmacokinetics and CSF Entry of Flurazepam in Dogs

Interaction of propoxyphene with diazepam, alprazolam and lorazepam.

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