Distribution of Fluphenazine and Its Metabolites in Brain Regions and Other Tissues of the Rat

Aravagiri, Manickam; Marder, Stephen R.; Yuwiler, Arthur; Midha, K. K.; Kula, Nora S.; Baldessarini, Ross J.

doi:10.1038/sj.npp.1380288

Cited by 10 publications

(7 citation statements)

References 30 publications

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“…When drugs are substrates of P-gp, the brain to blood concentration ratios vary widely for drugs with similar physicochemical properties. Animal studies found ratios ranging from 0.22 for risperidone [44] to 34 for fluphenazine [42]. Despite highly variable ratios of brain to blood concentrations of the different neuropsychiatric drugs, animal studies have shown that steady-state concentrations in blood correlate well with concentrations in brain, and much better than they correlate to the prescribed dosages.…”

Section: Drug Concentrations In Brain and Cerebrospinal Fluidmentioning

confidence: 99%

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

Bergemann²,

et al. 2017

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Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

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Section: Drug Concentrations In Brain and Cerebrospinal Fluidmentioning

confidence: 99%

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

Bergemann²,

et al. 2017

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“…Another issue is that these lipophilic drugs are often concentrated in tissues such that adipocytes could be exposed to higher levels than those observed in serum. The tissue concentration of butyrophenone, for example, is 22-fold higher than plasma (Tsuneizumi et al, 1992), and trifluoperazine-sulfoxide accumulates to reach 450 times higher levels in tissues than in blood (Aravagiri et al, 1995). However, studies have shown that certain SGAs, such as olanzapine and risperidone, do not reach high concentrations in adipose tissue (Aravagiri et al, 1998) and the clearance seems to occur faster than with other tissues in rats (Aravagiri et al, 1998(Aravagiri et al, , 1999.…”

Section: Discussionmentioning

confidence: 96%

Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

Vestri

Maianu

Moellering

et al. 2006

Neuropsychopharmacol

140

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Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 mM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 mM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by B40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by B50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These effects of SGAs on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes. Neuropsychopharmacology (2007) 32, 765-772.

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“…As a consequence, brain to plasma concentration ratios vary widely for psychotropic drugs with similar physicochemical properties. Animal studies found ratios from 0.22 for risperidone [ 29 ] to 34 for fl uphenazine [ 27 ] .…”

Section: Drug Concentration In Blood and Brainmentioning

confidence: 99%

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011

Hiemke¹,

et al. 2011

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than 5 decades [ 521 , 522 ] , growing evidence suggests that improving the way the available medications are administered may bring substantial benefi t to patients [ 45 ] . Evidence-based guidelines for optimum treatment have been published during the last decade [ 23 , 46 , 101 , 204 , 205 , 221 , 234 , 254 , 276 , 284 , 582 , 585 ,748]. A valuable tool for tailoring the dosage of the prescribed medication(s) to the individual characteristics of a patient is therapeutic drug monitoring (TDM). The major reason to use TDM for the guidance of psychopharmacotherapy is the Introduction ▼ In psychiatry, around 130 drugs are now available which have been detected and developed during the last 60 years [ 54 ] . These drugs are eff ective and essential for the treatment of many psychiatric disorders and symptoms. Despite enormous medical and economic benefi ts, however, therapeutic outcomes are still far from satis factory for many patients [ 5 , 6 , 396 , 661 ] . Therefore, after having focused clinical research on the development of new drugs during more Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defi ned ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrateand inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profi t from such a joint eff ort. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. considerable interindividual variability in the pharmacokinetic properties of the patient [ 524 , 526 ] . At the very same dose, a more than 20-fold interindividual variation in the medication's steady state concentration in the body may result, as patients diff er in their ability to absorb, distribute, metabolize and excrete drugs due to concurrent disease, age, concomitant medication or genetic peculiarities [ 61 , 94 , 310 , 311 , 334 , 335 , 374 ] . Diff erent formulations of the same medication may also infl uence the degree and temporal pattern of absorption and, hence, medication concentrations in the body. TDM uses the quantification of drug concent...

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Distribution of Fluphenazine and Its Metabolites in Brain Regions and Other Tissues of the Rat

Cited by 10 publications

References 30 publications

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011

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