Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression

Hreiche, Raymond; Mégarbane, Bruno; Pirnay, Stéphane; Borron, Stephen W.; Monier, Claire; Risède, Patricia; Milan, Nathalie; Descatoire, Véronique; Pessayre, Dominique; Baud, Frédéric J.

doi:10.1016/j.taap.2006.09.011

Cited by 11 publications

(33 citation statements)

References 37 publications

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“…Buprenorphine is known not to induce changes in blood gases (Hreiche et al, 2006) that could significant alter the blood oxygenation level Translation of the Buprenorphine PhMRI Response dependent signal. Therefore, it is unlikely that the observed differences arise from buprenorphine-induced physiologic adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Becerra

Upadhyay

Chang

et al. 2013

J Pharmacol Exp Ther

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Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial m-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development.

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Section: Discussionmentioning

confidence: 99%

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Becerra

Upadhyay

Chang

et al. 2013

J Pharmacol Exp Ther

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“…8 In rats, induction of CYP3A by dexamethasone increased plasma norbuprenorphine concentrations but did not result in respiratory depression following high-dose buprenorphine. 45 Since the central nervous system activity of drug metabolites relies both on their formation (metabolism) and their accessibility to the brain (diffusion or transport across the blood-brain barrier), genetic variants or drug interactions with metabolizing enzymes and/or transport proteins could potentially affect the clinical response to buprenorphine via its metabolites. For example, norbuprenorphine but not buprenorphine is a substrate for the brain efflux transporter P-glycoprotein.…”

Section: Discussionmentioning

confidence: 99%

Buprenorphine Metabolites, Buprenorphine-3-glucuronide and Norbuprenorphine-3-glucuronide, Are Biologically Active

et al. 2011

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Background The long-lasting high affinity opioid buprenorphine has complex pharmacology including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacological activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine. Methods Competitive inhibition of radioligand binding to human mu, kappa, delta opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in Swiss Webster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing. Results Buprenorphine-3-glucuronide had high affinity for human mu (Ki = 4.9±2.7 pM), delta (Ki = 270±0.4 nM), and nociceptin (Ki = 36±0.3 μM) but not kappa receptors. Norbuprenorphine-3-glucuronide had affinity for human kappa (Ki = 300±0.5 nM) and nociceptin (Ki= 18±0.2 μM) but not mu or delta receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation. Conclusions Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.

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“…In vivo quantification of benzodiazepine receptors (BzR) is possible with Positron Emission Tomography (PET) imaging using 11 C-flumazenil, a reversible BzR antagonist. 14 11 C-flumazenil has been used to quantify the engagement of BzR by different pharmacological doses of benzodiazepines.…”

Section: Introductionmentioning

confidence: 99%

“…14 11 C-flumazenil has been used to quantify the engagement of BzR by different pharmacological doses of benzodiazepines. 15,16 Moreover, 11 C-flumazenil PET imaging has been widely used to investigate regulation of BzRs in various pathological conditions such as epilepsy, 17 Alzheimer disease, 18 multiple sclerosis, 19 or ischemic stroke. 20 11 C-flumazenil benefits from extensive research to validate pharmacokinetic models and quantitatively describe the availability of BzR in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Several PET radioligands have been developed for quantification of opioid receptors (ORs) in the living brain. 25 The MOR 11 C-carfentanil has been useful to investigate the dose and time-dependent occupancy of MORs by buprenorphine in humans. 25 We recently validated 11 C-buprenorphine in rodents and non-human primates as a mean to specifically address the neuropharmacokinetics and binding of buprenorphine to its CNS targets in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Brain PET imaging using ¹¹C-flumazenil and ¹¹C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level

Auvity,

Vodovar,

Goutal

et al. 2023

J Cereb Blood Flow Metab

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Among opioids, buprenorphine presents a favorable safety profile with a limited risk of respiratory depression. However, fatalities have been reported when buprenorphine is combined to a benzodiazepine. Potentiation of buprenorphine interaction with opioid receptors (ORs) with benzodiazepines, and/or vice versa, is hypothesized to explain this drug-drug interaction (DDI). The mutual DDI between buprenorphine and benzodiazepines was investigated at the neuroreceptor level in nonhuman primates (n = 4 individuals) using brain PET imaging and kinetic modelling. The binding potential (BPND) of benzodiazepine receptor (BzR) was assessed using 11C-flumazenil PET imaging before and after administration of buprenorphine (0.2 mg, i.v.). Moreover, the brain kinetics and receptor binding of buprenorphine were investigated in the same individuals using 11C-buprenorphine PET imaging before and after administration of diazepam (10 mg, i.v.). Outcome parameters were compared using a two-way ANOVA. Buprenorphine did not impact the plasma nor brain kinetics of 11C-flumazenil. 11C-flumazenil BPND was unchanged following buprenorphine exposure, in any brain region (p > 0.05). Similarly, diazepam did not impact the plasma or brain kinetics of 11C-buprenorphine. 11C-buprenorphine volume of distribution ( VT) was unchanged following diazepam exposure, in any brain region (p > 0.05). To conclude, our PET imaging findings do not support a neuropharmacokinetic or neuroreceptor-related mechanism of the buprenorphine/benzodiazepine interaction.

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Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression

Cited by 11 publications

References 37 publications

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Buprenorphine Metabolites, Buprenorphine-3-glucuronide and Norbuprenorphine-3-glucuronide, Are Biologically Active

Brain PET imaging using ¹¹C-flumazenil and ¹¹C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level

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Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression

Cited by 11 publications

References 37 publications

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Buprenorphine Metabolites, Buprenorphine-3-glucuronide and Norbuprenorphine-3-glucuronide, Are Biologically Active

Brain PET imaging using 11C-flumazenil and 11C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level

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Brain PET imaging using ¹¹C-flumazenil and ¹¹C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level