Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 3A4 Enzyme and Relevant Drug Interactions: Review of Articles

Review Article

Austin J Psychiatry Behav Sci. 2016; 3(2): 1054.

Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 3A4 Enzyme and Relevant Drug Interactions: Review of Articles

Ayano G*

Research and Training Department, A Manuel Mental Specialized Hospital, Ethiopia

*Corresponding author: Getinet Ayano, Research and Training Department, A Manuel Mental Specialized Hospital, Addis Ababa, Ethiopia

Received: June 23, 2016; Accepted: August 30, 2016; Published: September 06, 2016

Abstract

Psychotropic medications metabolized by cytochromes P450 (CYP) 3A4 are reviewed and the possible relevance of this metabolism to drug-drug interactions is discussed. Cytochrome P4503A4 (CYP3A4) is the most prevalent of all Cytochromes P450 (CYPs) enzymes. It is found in large quantities in the liver and in the intestine, and involved in the metabolism of hundred of drugs including antipsychotics, mood stabilizers, hypnotics, anti anxiety drugs, antidepressants , calcium channel blockers, steroids and opiate analgesics. It is responsible for the metabolism of more than 50% of the commonly prescribed drugs. CYP3A4 metabolizes typical antipsychotic medications.

Haloperidol, perphenazine, aripiprazole, quetiapine, risperidone and ziprasidone from second generation antipsychotics. Amitriptyline, imipramine, clomipramine, citalopram, escitalopram, paroxetine, fluexetine, venalafaxine, trazodone, buspirone, nefazodone and mirtazapine are antidepressants which are metabolized by CYP3A4. Alprazolam, diazepam, medazolam, temazepam, lorazepam and clonazepam are among the common benzodiazepines which are primarily metabolized by CYP3A4. Nefazodon, Fluoxetine, clarithromycin, telithromycin, Ketokonazole, itraconazole, fluvoxamine, nefinavir valerian, milk thistle, grape fruit juice and gingko biloba, are inhibiters of CYP3A4 enzyme. Phenytoin, carbamaepine, oxycarbazepine, phenobarbitone, prednsolone, john’s wort, rifampicin and efavirnaz are common inducers of CYP3A4 enzyme.

Keywords: Cytochromes P450 (CYP) 3A4; Antipsychotics; Tricyclic antidepressants; Selective serotonin reuptake inhibitors; Benzodiazepines; Polymorphism; Antibiotics; Opiates

Introduction

Cytochromes P450 (CYPs) enzymes consist of a super family of heme-containing proteins localized within the endoplasmic reticulum of the liver as well as in the brain and periphery and are responsible for the metabolism of widest range of drugs [1-4].

Cytochrome P450 3A4 (CYP3A4) is the most prevalent of all Cytochromes P450 (CYPs) enzymes. It is found in large quantities in the liver and in the intestine and involved in the metabolism of hundred of drugs including antipsychotics, mood stabilizers, hypnotics, antianxiety drugs, antidepressants, calcium channel blockers, steroids and opiate analgesics [1,2].

Cytochrome P450 3A4 (CYP3A4) enzyme polymorphism is responsible for observed variations in drug response among patients of differing ethnic origins. Genetic variability (polymorphism) in these enzymes may influence a patient’s response to commonly prescribed drug classes, including antipsychotics, beta blockers and antidepressants [5-8].

The CYP3A family is the most abundant subfamily of the CYP isoforms in the liver. CYP3A4 is mainly located in the liver and small intestine and is the most abundant cytochrome in these organs. Cytochrome CYP3A4 is responsible for the metabolism of more than 50% of medicines. CYP3A4 activity is absent in new-borns but reaches adult levels at around one year of age [3-5].

The CYP3A4 protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs that are used today [1-4].

Psychotropic and other Drugs Metabolized by CYP3A4

Antipsychotic medications metabolized by CYP3A4

Both first generation and second generation antipsychotics are substrates of CYP3A4 enzyme. It metabolizes typical antipsychotic medications, such as haloperidol and perphenazine [9,10] and aripiprazole [12], quetiapine [13,14], risperidone [15-17] and ziprasidone [18] from second generation antipsychotics.

Antidepressant medications metabolized by CYP3A4

CYP3A4 metabolizes Selective Serotonin Reuptake Inhibitors (SSRIs) such as citalopram, escitalopram, paroxetine, and fluexetine [19-23]. CYP3A4 also metabolizes selective Serotonin- Norepinephrine Reuptake Inhibitors (SNRIs) such as venalafaxine and trazodone [10,24].

Tricyclic Antidepressant (TCAs,) including amitriptyline, clomipramine and imipramine are metabolized by CYP3A4 enzymes [25-31].

Other Antidepressants such as buspirone Nefazodone and Mirtazapine are metabolized by CYP3A4 [32-34].

Mood stabilizer medications metabolized CYP3A4

From mood stabilizers carbamaepine is primarily metabolized by P450 3A4 [35-37] and other mood stabilizers including valproate, lamotrigine and topiramate are not metabolized by CYP3A4 [10,38- 40]. Lithium is mood stabilizers which are purely renally excreted, with no hepatic metabolic component. It lacks any inhibitory or inductive capabilities.

Benzodiazepines metabolized by CYP3A4

CYP3A4 is also involved in metabolism of Benzodiazepines.

Alprazolam, diazepam, medazolam, temazepam, lorazepam and clonazepam are common benzodiazepine metabolized by CYP3A4 [10, 41,42].

Opiates metabolized by CYP3A4

Several of opiates including codeine, methadone, fentanyl and burenorphine are metabolized by CYP3A4 [41,42].

Hypnotics metabolized by CYP3A4

CYP3A4 is also involved in metabolism of hypnotics. Zopiclone, Zaleplon and zolpidem are commonly hypnotics called “Z” drugs are metabolized by CYP3A4 [10, 41,42].

Antibiotics metabolized by CYP3A4

The macrolide antibiotics such as erythromycin, clarithromycin and telithromycin are metabolized by CYP3A4 [41,42].

Phosphodiesters (PDEs) inhibitors metabolized by CYP3A4

Phosphodiesters (PDEs) inhibitors such as sildenafil and tadalafil are metabolized by CYP3A4 [10,41,42] (Table 1 & Table 2).

Table 1: Common drugs metabolized by CYP3A4.





  

    
Group of drugs 

    
Drug name 

  

  

    
Antidepressants    (tricyclics)

    
Amitriptyline,    Imipramine, clomipramine

  

  

    
Antidepressants    (SSRIs)

    
citalopram,    escitalopram, paroxetine, fluexetine

  

  

    
Antidepressants    (SNRIs)

    
venalafaxine, trazodone

  

  

    
Antidepressants    (others)

    
buspirone    Nefazodone, Mirtazapine

  

  

    
Antipsychotics(first    generations)

    
haloperidol,    perphenazine

  

  

    
Antipsychotics(second    generations)

    
aripiprazole,    quetiapine, risperidone, ziprasidone

  

  

    
Benzodiazepines

    
Alprazolam,    diazepam, medazolam, temazepam, lorazepam , clonazepam

  

  

    
Opiates

    
codeine, methadone,    fentanyl, burenorphine

  

  

    
hypnotics

    
Zopiclone, Zaleplon,    zolpidem

  

  

    
Antibiotics

    
erythromycin,    clarithromycin, telithromycin

  

  

    
Phosphodiesters    (PDEs) inhibitors

    
sildenafil,    tadalafil

  









Table 1:  Common drugs metabolized by CYP3A4.

Table 2: Summary cytochrome CYP3A4 substrates, inhibitors and inducers.





  

    
Substrate 

    
    
Inhibitors 

    
inducers 

  

  

    
Aripiprazole

    
Erythromycin

    
Nefazodone

    
phenytoin

  

  

    
quetiapine,

    
clarithromycin

    
Fluoxetine,

    
carbamaepine

  

  

    
risperidone,

    
,telithromycin

    
clarithromycin

    
oxycarbazepine,

  

  

    
ziprasidone

    
sildenafil

    
telithromycin

    
phenobarbitone

  

  

    
codeine

    
tadalafil

    
Ketokonazole

    
prednsolone

  

  

    
methadone,

    
Amitriptyline

    
itraconazole

    
john's wort

  

  

    
fentanyl

    
Imipramine

    
fluvoxamine

    
rifampicin

  

  

    
burenorphine

    
clomipramine

    
nefinavir

    
efavirnaz

  

  

    
Alprazolam

    
citalopram

    
valerian

    
  

  

    
Diazepam

    
escitalopram

    
milk thistle

    
  

  

    
Medazolam

    
paroxetine

    
grape fruit juice

    
  

  

    
Temazepam

    
fluexetine

    
gingko biloba

    
  

  

    
lorazepam

    
venalafaxine

    
    
  

  

    
clonazepam

    
trazodone

    
    
  

  

    
Zopiclone

    
buspirone

    
    
  

  

    
Zaleplon

    
Nefazodone

    
    
  

  

    
Zolpidem

    
Mirtazapine

    
    
  

  

    
perphenazine

    
haloperidol

    
    
  









Table 2:  Summary cytochrome CYP3A4 substrates, inhibitors and inducers.

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Citation: Ayano G. Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 3A4 Enzyme and Relevant Drug Interactions: Review of Articles. Austin J Psychiatry Behav Sci. 2016; 3(2): 1054. ISSN : 2381-9006