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Holladay, John W.; Dewey, Michael J.; Yoo, Sun Dong

doi:10.1023/a:1016005529420

Cited by 12 publications

(9 citation statements)

References 14 publications

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“…[32][33][34] According to the packing insert (Imipramine hydrochloride, Novartis Pharma, 2006, Tokyo, Japan), after oral dosing of 75 mg imipramine, the maximum plasma concentrations of imipramine and desipramine are 70 ng/ml (0.25 mM) and 29 ng/ml (0.11 mM), respectively. Although the plasma or brain concentrations of other psychotropic drugs are unknown, it can be speculated that the expected brain concentrations of fluoxetine, imipramine, and desipramine are comparable to or higher than the K i values (1-16 mM).…”

Section: Discussionmentioning

confidence: 99%

Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain

Niwa

Okada

Hiroi

et al. 2008

Biological & Pharmaceutical Bulletin

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Progesterone (PROG) not only is one of the female steroid hormones secreted from the placenta and corpus luteum but also has various functions in the central nervous system as a neurosteroid in the brain.1,2) PROG has the ability to increase myelin-specific protein levels and to enhance the g-aminobutyric acid (GABA)-induced chloride current, 2,3) and the PROG metabolites, 3a-hydroxy-5a-pregnan-20-one (allopregnanolone, ALLO) and 3a,5a-tetrahydrodeoxycorticosterone, act as positive allosteric modulators of GABA type A receptors, and thereby reduce brain excitability and elicit sedative-hypnotic, anxiolytic, and anticonvulsant effects. 4)These neurosteroids are eliminated via the metabolic pathways, including the hydroxylation at position C21. 5)Cytochrome P450s (CYP) comprise a superfamily of enzymes that catalyze the oxidation of a wide variety of xenobiotic chemicals including drugs, carcinogens, and steroids. [6][7][8] In spite of the fact that CYP2D6 constitutes only 2-9% of constitutively expressed hepatic P450s among humans, 9,10) it plays important roles in the metabolism of a wide range of therapeutic agents, including drugs affecting the central nervous system. 5,8,11,12) Interestingly, CYP2D6 is expressed in the human brain, especially the midbrain, 13) as well as in the liver. In addition, CYP2D4 mRNA is expressed in the rat brain, 14,15) and the reverse transcriptase-polymerase chain reaction (RT-PCR) product from CYP2D4, the predominant CYP2D isoform in the rat brain, is more abundant in the cerebellum, striatum, pons, and medulla oblongata. 16)However, the physiological and pharmacological functions of CYP2D isoforms in the brain are still unknown.We have demonstrated that CYP2D6 catalyzes the 2b, 6b-, 16a-, and 21-hydroxylation of PROG, 17,18) and that PROG 2b-and 21-hydroxylation activities in rat brain microsomes are completely inhibited by CYP2D antibodies, suggesting that CYP2D may be involved in the regulation (metabolism and/or synthesis) of endogenous neuroactive steroids, such as PROG and its derivatives, in the brain.18) Additionally, we have reported that the 21-hydroxylation of ALLO as well as PROG and 17a-PROG is catalyzed by CYP2D isoforms in the brain. 5,15) Many of the psychotropic drugs, including fluoxetine (a selective serotonin reuptake inhibitor, SSRI), imipramine (a tricyclic antidepressant and a serotonin and noradrenaline reuptake inhibitor), and desipramine (a noradrenaline reuptake inhibitor), are metabolized by CYP2D and/or inhibit the CYP2D-mediated metabolic activities. 8,15,[19][20][21][22][23] One of the dopamine uptake sites in the brain displays high affinity for dopamine uptake inhibitors such as mazindol, a noradrenaline reuptake inhibitor. 24,25) The other site displays rather high affinity for piperizine derivatives and has been termed the piperazine acceptor site. 26) GBR12909 (vanoxerine) is a potent inhibitor of both the binding of GBR12935, a piperizine derivative, and CYP2D6 activity. 27) We have demonstrated that the GBR12935 binding is reduced by CYP2D su...

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Section: Discussionmentioning

confidence: 99%

Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain

Niwa

Okada

Hiroi

et al. 2008

Biological & Pharmaceutical Bulletin

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“…Holladay et al studied steady-state kinetics of imipramine in transgenic mice expressing serum AGP levels about 9-fold elevated over normal. [38,39] It was found that of the many physiologic derangements experienced by cigarette smokers, possible elevation of serum concentrations of the acute-phase reactant a, alpha-1-acid glycoprotein (AAG) is of particular interest because AAG is a major binding protein for several basic drugs, including lidocaine, amitriptyline, verapamil, and perhaps others. [40] It is generally assumed that in plasma, acidic drugs are mainly bound to human serum albumin.…”

Section: Agp Drug Binding In Disease Statesmentioning

confidence: 99%

Acute-Phase Proteins: Alpha -1- Acid Glycoprotein

Tesseromatis¹,

Alevizou²,

Tigka³

et al. 2011

Acute Phase Proteins - Regulation and Functions of Acute Phase Proteins

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“…The most widely used methods involve high-performance liquid chromatography (HPLC) with UV detection [4,11,12,[14][15][16][17][18]. FL/NORFL levels can also be measured in biological samples using gas chromatography (GC) coupled with MS [21,22], flame ionization [23], electron capture [24,25] or nitrogen phosphorus detection [26].…”

Section: Introductionmentioning

confidence: 99%

Comparison of liquid chromatography with fluorescence detection to liquid chromatography–mass spectrometry for the determination of fluoxetine and norfluoxetine in human plasma

Kovačević

Pokrajac

Miljković

et al. 2006

Journal of Chromatography B

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Abstract: Elevated serum AAG impedes the transport of imipramine and desipramine into the brain. Further, in the presence of elevated serum AAG levels, imipramine and desipramine concentrations in the brain did not correlate with their respective concentrations in the serum.

Cited by 12 publications

References 14 publications

Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain

Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain

Acute-Phase Proteins: Alpha -1- Acid Glycoprotein

Comparison of liquid chromatography with fluorescence detection to liquid chromatography–mass spectrometry for the determination of fluoxetine and norfluoxetine in human plasma

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