Histamine H1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers

Sato, Hirotoshi; Ito, Chihiro; Hiraoka, Kotaro; Tashiro, Masato; Shibuya, Kazuhiko; Funaki, Y.; Yoshikawa, Takeo; Iwata, Ren; Matsuoka, Hiroo; Yanai, Kazuhiko

doi:10.1007/s00213-015-4002-2

Cited by 31 publications

(20 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, it can be observed that the histamine H1 RO (gray line) is comparable to D2 RO (black line). The considerable binding to H1 receptor has been suggested to be responsible for the sedative effects of antipsychotics …”

Section: Resultsmentioning

confidence: 99%

“…For instance, clozapine is one of the antipsychotics that is most prone to induce metabolic disturbance such as weight gain and diabetes, which could be attributed to its high affinity to both serotonin 5‐HT 2C and hypothalamic histamine H1 receptors . Also, RO at cortical H1 receptors contributes to the prominent sedative effect of clozapine . Clozapine's high affinity to both muscarinic M1 and 5‐HT 2A receptors could have contributed to its low propensity to induce motor side effects .…”

Section: Discussionmentioning

confidence: 99%

“…First, active drug transport across the BBB was not incorporated, although in vivo evidence from rat studies did indicate the involvement of active transports for quetiapine . In fact, the histamine H1 RO values in the cortex did not correlate with the plasma quetiapine concentrations in humans, indicating the limitation of predicting CNS RO based solely on plasma PK. Second, the contribution of active metabolites to the RO level was not considered.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human

Wong

Centanni

Lange

2019

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Receptor occupancy (RO) is a translational biomarker for assessing drug efficacy and safety. We aimed to apply a physiologically based pharmacokinetic (PBPK) modeling approach to predict the brain dopamine D2 RO time profiles of antipsychotics. Clozapine and risperidone were modeled together with their active metabolites, norclozapine and paliperidone, First, in PK‐Sim a rat PBPK model was developed and optimized using literature plasma PK data. Then, blood‐brain barrier parameters including the expression and efflux transport kinetics of P‐glycoprotein were optimized using literature microdialysis data on brain extracellular fluid (brainECF), which were further adapted when translating the rat PBPK model into the human PBPK model. Based on the simulated drug and metabolite concentrations in brainECF, drug‐D2 receptor binding kinetics (association and dissociation rates) were incorporated in MoBi to predict RO. From an extensive literature search, 32 plasma PK data sets (16 from rat and 16 from human studies) and 23 striatum RO data sets (13 from rat and 10 from human studies) were prepared and compared with the model predictions. The rat PBPK‐RO model adequately predicted the plasma concentrations of the parent drugs and metabolites and the RO levels. The human PBPK‐RO model also captured the plasma PK and RO levels despite the large interindividual and interstudy variability, although it tended to underestimate the plasma concentrations and RO measured at late time points after risperidone dosing. The developed human PBPK‐RO model was successfully applied to predict the plasma PK and RO changes observed after risperidone dose reduction in a clinical trial in schizophrenic patients.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human

Wong

Centanni

Lange

2019

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…A previous study reported that clinically observed H 1 RO by antihistamines can be estimated by the integration of preclinical data on pharmacokinetic/pharmacodynamics parameters . Since the modeling and simulation are incomplete at this moment, brain H 1 RO by [ 11 C]‐doxepin PET has been utilized as an index of the sedative potential of H 1 antagonists including antipsychotics and antidepressants . The H 1 RO of first‐ and second‐generation antihistamines has been measured by several PET research groups, and a classification of these drugs has been proposed according to the level of H 1 RO .…”

Section: Discussionmentioning

confidence: 99%

Brain histamine H₁ receptor occupancy after oral administration of desloratadine and loratadine

Nakamura

Hiraoka

Harada

et al. 2019

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

Some histamine H 1 receptor (H 1 R) antagonists induce adverse sedative reactions caused by blockade of histamine transmission in the brain. Desloratadine is a second‐generation antihistamine for treatment of allergic disorders. Its binding to brain H 1 Rs, which is the basis of sedative property of antihistamines, has not been examined previously in the human brain by positron emission tomography (PET). We examined brain H 1 R binding potential ratio (BPR), H 1 R occupancy (H 1 RO), and subjective sleepiness after oral desloratadine administration in comparison to loratadine. Eight healthy male volunteers underwent PET imaging with [ 11 C]‐doxepin, a PET tracer for H 1 Rs, after a single oral administration of desloratadine (5 mg), loratadine (10 mg), or placebo in a double‐blind crossover study. BPR and H 1 RO in the cerebral cortex were calculated, and plasma concentrations of loratadine and desloratadine were measured. Subjective sleepiness was quantified by the Line Analogue Rating Scale (LARS) and the Stanford Sleepiness Scale (SSS). BPR was significantly lower after loratadine administration than after placebo (0.504 ± 0.074 vs 0.584 ± 0.059 [mean ± SD], P < 0.05), but BPR after desloratadine administration was not significantly different from BPR after placebo (0.546 ± 0.084 vs 0.584 ± 0.059, P = 0.250). The plasma concentration of loratadine was negatively correlated with BPR in subjects receiving loratadine, but that of desloratadine was not correlated with BPR. Brain H 1 ROs after desloratadine and loratadine administration were 6.47 ± 10.5% and 13.8 ± 7.00%, respectively ( P = 0.103). Subjective sleepiness did not significantly differ among subjects receiving the two antihistamines and placebo. At therapeutic doses, desloratadine did not bind significantly to brain H 1 Rs and did not induce any significant sedation.

show abstract

“…It shares characteristics with dopaminergic (D1, D2, D3, D4 receptor) antagonists, adrenergic (α1, α2 receptor) antagonists, 5-HT1A partial agonists, high affinity 5-HT2A partial antagonists, and potentially shares properties with histamine (H1 receptor) antagonists. 2 – 4 The main indications for quetiapine are schizophrenia, bipolar disorder, and delirium.…”

Section: Discussionmentioning

confidence: 99%

Reversible global aphasia as a side effect of quetiapine: a case report and literature review

Chien¹,

Huang²,

Hsieh³

2017

NDT

View full text Add to dashboard Cite

Quetiapine is an atypical antipsychotic agent which is also prescribed for delirium due to its anti-dopaminergic effects; aphasia is an unusual side effect associated with the drug. Here, we report the case of an 83-year-old woman who was prescribed quetiapine (50 mg per day) for delirium. Unexpected, global aphasia occurred 3 days after treatment began. Complete recovery occurred following discontinuation of the drug. A brain computed tomography scan excluded intracranial hemorrhage and the laboratory results confirmed that no exacerbation of infection or electrolyte imbalances were present. During the aphasic episode, the patient’s condition did not deteriorate and no new neurological symptoms occurred. We suspect that the occurrence of aphasia was directly due to an adverse reaction to quetiapine. To our knowledge, this is the first case report of reversible, global aphasia as a side effect of quetiapine. We propose that this occurrence of aphasia may be due to the action of quetiapine as a dopamine receptor antagonist. Clinicians should use quetiapine with caution, especially in elderly patients. On observation of aphasia, a review of the patient’s medical history is required to assess for the usage of quetiapine.

show abstract

Histamine H1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers

Abstract: Olanzapine and quetiapine have high H1RO values in the human brain under their clinical minimum doses. This study provides a foundation of the properties by which new-generation antipsychotics block the central histaminergic system in humans.

Cited by 31 publications

References 53 publications

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human

Brain histamine H₁ receptor occupancy after oral administration of desloratadine and loratadine

Reversible global aphasia as a side effect of quetiapine: a case report and literature review

Contact Info

Product

Resources

About

Histamine H1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers

Abstract: Olanzapine and quetiapine have high H1RO values in the human brain under their clinical minimum doses. This study provides a foundation of the properties by which new-generation antipsychotics block the central histaminergic system in humans.

Cited by 31 publications

References 53 publications

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human

Brain histamine H1 receptor occupancy after oral administration of desloratadine and loratadine

Reversible global aphasia as a side effect of quetiapine: a case report and literature review

Contact Info

Product

Resources

About

Brain histamine H₁ receptor occupancy after oral administration of desloratadine and loratadine