Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2

Ball, S.; Ahern, Dennis; Scatina, JoAnn; Kao, John Y.

doi:10.1046/j.1365-2125.1997.00591.x

Cited by 96 publications

(54 citation statements)

References 5 publications

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“…Compared with typical CYP2D6 inhibitors, the inhibitory effect of CBD on recombinant CYP2D6-mediated activity is comparable to those of (S)-nolfluoxetine (K i ϭ 0.84 M), (S)-fluoxetine (K i ϭ 1.27 M) (Shen et al, 2007), desipramine (K i ϭ 1.0 M), and imipramine (K i ϭ 1.4 M) (Niwa et al, 2008). The inhibitory effect of CBD on HLM-mediated CYP2D6 activity is as potent as those of (S,R)-fluoxetine (K i ϭ 1.6 M), desipramine (K i ϭ 1.7 M) (Ball et al, 1997), and 3,4-methylenedioxyamphetamine (K i ϭ 1.8 M) (Wu et al, 1997). In addition, the potency of CBD against CYP2D6 inhibition in HLMs is slightly lower than that of MDMA (K i ϭ 0.6 M), but it is much higher than those of (ϩ)-methamphetamine and (Ϫ)-amphetamine (K i Ϸ 25 M) (Wu et al, 1997).…”

Section: Discussionmentioning

confidence: 81%

Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6

Yamaori¹,

Okamoto²,

Yamamoto³

et al. 2011

Drug Metab Dispos

135

104

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Section: Discussionmentioning

confidence: 81%

Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6

Yamaori¹,

Okamoto²,

Yamamoto³

et al. 2011

Drug Metab Dispos

135

104

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“…There are few reports comparing the inhibition type of imipramine and desipramine except that both imipramine and desipramine competitively inhibit venlafaxine O-demethylation by human liver microsomes. 38) In addition, GRB12909 inhibited the 21-hydroxylation of PROG and ALLO by CYP2D4 and CYP2D6, even though CYP3A4 is the major enzyme responsible for the biotransformation of GBR12909. 39) It is well known that quinidine, a typical inhibitor of CYP2D, is predominantly metabolized by CYP3A4.…”

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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“…However, recent in vivo studies from healthy volunteers indicated that a potent CYP2D6 inhibitor, paroxetine (Crewe et al, 1992;Ball et al, 1997;Lam et al, 2002) significantly increased plasma concentrations of (R)-and (S)-methadone (Begre et al, 2002). In addition, in two poor metabolizers of CYP2D6, tested in 10 subjects, only (S)-methadone but not (R)-methadone was increased by paroxetine (Begre et al, 2002).…”

mentioning

confidence: 99%

INVOLVEMENT OF CYP3A4, CYP2C8, AND CYP2D6 IN THE METABOLISM OF (R)- AND (S)-METHADONE IN VITRO

Wang¹,

DeVane²

2003

Drug Metab Dispos

140

132

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:To clarify the oxidative metabolism of methadone (R)-and (S)-enantiomers, the depletion of parent (R)-and (S)-methadone and the formation of racemic 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine were studied using human liver microsomes and recombinant cytochrome P450 enzymes. Based on studies with isoform-selective chemical inhibitors and expressed enzymes, CYP3A4 was the predominant enzyme involved in the metabolism of (R)-methadone. However, it has different stereoselectivity toward (R)-and (S)-methadone. In recombinant CYP3A4, the metabolic clearance of (R)-methadone was about 4-fold higher than that of (S)-methadone. CYP2C8 is also involved in the metabolism of methadone, but its contribution to the metabolism of (R)-methadone was smaller than that of CYP3A4. But for the metabolism of (S)-methadone, the roles of CYP2C8 and CYP3A4 appeared equal. Although CYP2D6 is involved in the metabolism of (R)-and (S)-methadone, its role was smaller compared with CYP3A4 and CYP2C8. Using clinically relevant concentrations of ketoconazole (1 M, selective CYP3A4 inhibitor), trimethoprim (100 M, selective CYP2C8 inhibitor), and paroxetine (5 M, potent CYP2D6 inhibitor), these inhibitors decreased the hepatic metabolism of (R)-[(S)-]methadone by 69% (47%), 22% (51%), and 41% (77%), respectively. However, inhibition of the metabolism of (R)-and (S)-methadone by paroxetine was due to inhibition not only of CYP2D6, but also CYP3A4 and, to a minor extent, CYP2C8. The present in vitro findings indicated that CYP3A4, CYP2C8, and CYP2D6 are all involved in the stereoselective metabolism of methadone (R)-and (S)-enantiomers. These data suggest that coadministration of inhibitors of CYP3A4 and CYP2C8 may produce clinically significant drug-drug interactions with methadone.

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Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2

Cited by 96 publications

References 5 publications

Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6

Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6

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

INVOLVEMENT OF CYP3A4, CYP2C8, AND CYP2D6 IN THE METABOLISM OF (R)- AND (S)-METHADONE IN VITRO

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