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'''Cytochrome P450 2D6''' (CYP2D6), a member of the [[cytochrome P450]] mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of [[xenobiotic]]s in the body. Whilst CYP2D6 is involved in the oxidation of a wide range of substrates of all the [[Cytochrome P450|CYP]]s, there is considerable variability in its expression in the liver. The gene is located near two cytochrome P450 [[pseudogene]]s on chromosome 22q13.1. [[alternative splicing|Alternatively spliced]] transcript variants encoding different [[isoform]]s have been found for this gene.<ref>{{cite web | title = Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1565| accessdate = }}</ref>
'''Cytochrome P450 2D6''' ('''CYP2D6''') is an [[enzyme]] that in humans is encoded by the ''CYP2D6'' [[gene]]. ''CYP2D6'' is primarily expressed in the [[liver]]. It is also highly expressed in areas of the [[central nervous system]], including the [[substantia nigra]].


==Genotype/phenotype variability==
CYP2D6, a member of the [[cytochrome P450]] mixed-function oxidase system, is one of the most important enzymes involved in the [[metabolism]] of [[xenobiotic]]s in the body. In particular, CYP2D6 is responsible for the metabolism and [[clearance (medicine)|elimination]] of approximately 25% of clinically used drugs, via the addition or removal of certain [[functional group]]s&nbsp;– specifically, [[hydroxylation]], [[demethylation]], and [[dealkylation]].<ref name="pmid19645588">{{cite journal | vauthors = Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF | title = New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme | journal = Drug Metabolism Reviews | volume = 41 | issue = 4 | pages = 573–643 | year = 2009 | pmid = 19645588 | doi = 10.1080/03602530903118729 }}</ref>  Other drugs, known as [[prodrug]]s, are activated by the action of CYP2D6. This enzyme also metabolizes several endogenous substances, such as [[serotonin|hydroxytryptamines]], [[neurosteroid]]s, and both [[m-tyramine|''m''-tyramine]] and [[tyramine|''p''-tyramine]] which CYP2D6 metabolizes into [[dopamine]] in the brain and liver.<ref name="pmid19645588"/><ref name="Brain CYP2D6">{{cite journal | vauthors = Wang X, Li J, Dong G, Yue J | title = The endogenous substrates of brain CYP2D | journal = European Journal of Pharmacology | volume = 724 | pages = 211–8 | date = February 2014 | pmid = 24374199 | doi = 10.1016/j.ejphar.2013.12.025 }}</ref>
CYP2D6 shows the largest [[phenotype|phenotypical]] variability amongst the CYPs, largely due to [[genetics|genetic]] [[polymorphism (biology)|polymorphism]]. The [[genotype]] accounts for normal, reduced and non-existent CYP2D6 function in subjects.  


The CYP2D6 function in any particular subject may be described as one of the following:
Considerable variation exists in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence, for drugs that are metabolized by CYP2D6 (that is, are CYP2D6 [[enzyme substrate|substrates]]), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers).  If a drug is metabolized too quickly, it may decrease the drug's [[Efficacy#Pharmacology|efficacy]] while if the drug is metabolized too slowly, toxicity may result.<ref name="pmid22185816"/>  So, the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6.<ref name="pmid22515611">{{cite journal | vauthors = Walko CM, McLeod H | title = Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment | journal = Pharmacogenomics | volume = 13 | issue = 6 | pages = 691–7 | date = April 2012 | pmid = 22515611 | doi = 10.2217/pgs.12.27 }}</ref>


*poor metaboliser - these subjects have little or no CYP2D6 function
Other drugs may function as [[enzyme inhibitor|inhibitor]]s of CYP2D6 activity or [[inducer]]s of CYP2D6 enzyme expression that will lead to decreased or increased CYP2D6 activity respectively.  If such a drug is taken at the same time as a second drug that is a CYP2D6 substrate, the first drug may affect the elimination rate of the second through what is known as a [[drug interaction|drug-drug interaction]].<ref name="pmid22185816">{{cite journal | vauthors = Teh LK, Bertilsson L | title = Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance | journal = Drug Metabolism and Pharmacokinetics | volume = 27 | issue = 1 | pages = 55–67 | year = 2012 | pmid = 22185816 | doi = 10.2133/dmpk.DMPK-11-RV-121 }}</ref>
*intermediate metabolizers - these subjects metabolize drugs at a rate somewhere between the poor and extensive metabolizers
*extensive metaboliser - these subjects have normal CYP2D6 function
*ultrarapid metaboliser - these subjects have multiple copies of the ''CYP2D6'' [[gene]] expressed, and therefore greater-than-normal CYP2D6 function


A patient's CYP2D6 phenotype is often clinically determined via the administration of [[debrisoquine]] (a selective CYP2D6 substrate) and subsequent plasma concentration assay of the debrisoquine [[metabolite]] (4-hydroxydebrisoquine). More recently, a "[[DNA microarray]]" has been developed, known as the [[AmpliChip CYP450 Test|AmpliChip]], which allows the automated determination of a patient's CYP2D6 (or [[CYP2C19]]) genotype.
== Gene ==


==Genetic basis of variability==
The gene is located near two cytochrome P450 [[pseudogene]]s on chromosome 22q13.1. [[alternative splicing|Alternatively spliced]] transcript variants encoding different [[isoform]]s have been found for this gene.<ref>{{cite web | title = Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1565 }}</ref>
The genetic basis for extensive and poor metaboliser variability is the ''CYP2D6'' [[allele]], located on [[chromosome 22]]. Subjects who possess certain allelic variants will show normal, decreased or no CYP2D6 function depending on the allele.


{| width="50%" border="0" align="center" cellpadding="2" cellspacing="2"  
== Genotype/phenotype variability ==
| colspan="2" bgcolor="#CCCCCC" | '''''CYP2D6'' allele and enzyme activity''' (after Droll ''et al''., 1998)
 
CYP2D6 shows the largest [[phenotype|phenotypical]] variability among the CYPs, largely due to [[genetics|genetic]] [[polymorphism (biology)|polymorphism]]. The [[genotype]] accounts for normal, reduced, and non-existent CYP2D6 function in subjects. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice.<ref name="PMID24413808" />
The CYP2D6 function in any particular subject may be described as one of the following:<ref name="pmid11851634">{{cite journal | vauthors = Bertilsson L, Dahl ML, Dalén P, Al-Shurbaji A | title = Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs | journal = British Journal of Clinical Pharmacology | volume = 53 | issue = 2 | pages = 111–22 | date = February 2002 | pmid = 11851634 | pmc = 1874287 | doi = 10.1046/j.0306-5251.2001.01548.x }}</ref>
* poor metabolizer – little or no CYP2D6 function
* intermediate metabolizers – metabolize drugs at a rate somewhere between the poor and extensive metabolizers
* extensive metabolizer – normal CYP2D6 function
* ultrarapid metabolizer – multiple copies of the ''CYP2D6'' gene are expressed, so greater-than-normal CYP2D6 function occurs
 
A patient's CYP2D6 phenotype is often clinically determined via the administration of [[debrisoquine]] (a selective CYP2D6 substrate) and subsequent plasma concentration assay of the debrisoquine [[metabolite]] (4-hydroxydebrisoquine).<ref name="pmid19102711">{{cite journal | vauthors = Llerena A, Dorado P, Peñas-Lledó EM | title = Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity | journal = Pharmacogenomics | volume = 10 | issue = 1 | pages = 17–28 | date = January 2009 | pmid = 19102711 | doi = 10.2217/14622416.10.1.17 }}</ref>
 
The type of CYP2D6 function of an individual may influence the person's response to different doses of drugs that CYP2D6 metabolizes. The nature of the effect on the drug response depends not only on the type of CYP2D6 function, but also on the extent to which processing of the drug by CYP2D6 results in a chemical that has an effect that is similar, stronger, or weaker than the original drug, or no effect at all. For example, if CYP2D6 converts a drug that has a strong effect into a substance that has a weaker effect, then poor metabolizers (weak CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects; conversely, if CYP2D6 converts a different drug into a substance that has a greater effect than its parent chemical, then ultrarapid metabolizers (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects.<ref name="pmid17708140">{{cite journal | vauthors = Lynch T, Price A | title = The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects | journal = American Family Physician | volume = 76 | issue = 3 | pages = 391–6 | date = August 2007 | pmid = 17708140 }}</ref>
 
== Genetic basis of variability ==
 
The genetic basis for CYP2D6-mediated metabolic variability is the ''CYP2D6'' [[allele]], located on [[chromosome 22]]. Subjects possessing certain allelic variants will show normal, decreased, or no CYP2D6 function, depending on the allele. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice.<ref name="PMID24413808">{{cite journal | vauthors = Dinama O, Warren AM, Kulkarni J | title = The role of pharmacogenomic testing in psychiatry: Real world examples | journal = The Australian and New Zealand Journal of Psychiatry | volume = 48 | issue = 8 | pages = 778 | date = August 2014 | pmid = 24413808 | doi = 10.1177/0004867413520050 }}</ref>
 
{| width="50%" border="0" cellpadding="2" cellspacing="2"
| colspan="2" bgcolor="#CCCCCC" | '''''CYP2D6'' enzyme activity for selected alles'''<ref name="Droll_1998"/><ref>{{cite web|url=http://www.cypalleles.ki.se/cyp2d6.htm| title= CYP2D6 allele nomenclature|accessdate=5 February 2016}}</ref>
|-
|-
| width="50%" bgcolor="#CCCCCC" | Allele
| width="50%" bgcolor="#CCCCCC" | Allele
| width="50%" bgcolor="#CCCCCC" | CYP2D6 activity
| width="50%" bgcolor="#CCCCCC" | CYP2D6 activity
|-  
|-
| bgcolor="#efefef" | ''CYP2D6*1''
| bgcolor="#efefef" | ''CYP2D6*1''
| bgcolor="#dfefff" | normal
| bgcolor="#dfefff" | normal
|-  
|-
| bgcolor="#efefef" | ''CYP2D6*3''
| bgcolor="#efefef" | ''CYP2D6*2''
| bgcolor="#dfefff" | none
| bgcolor="#dfefff" | normal
|-  
|-
| bgcolor="#efefef" | ''CYP2D6*4''
| bgcolor="#efefef" | ''CYP2D6*3''
| bgcolor="#dfefff" | none
| bgcolor="#dfefff" | none
|-  
|-
| bgcolor="#efefef" | ''CYP2D6*5''
| bgcolor="#efefef" | ''CYP2D6*4''
| bgcolor="#dfefff" | none
| bgcolor="#dfefff" | none
|-  
|-
| bgcolor="#efefef" | ''CYP2D6*9''
| bgcolor="#efefef" | ''CYP2D6*5''
| bgcolor="#dfefff" | decreased
| bgcolor="#dfefff" | none
|-  
|-
| bgcolor="#efefef" | ''CYP2D6*10''
| bgcolor="#efefef" | ''CYP2D6*6''
| bgcolor="#dfefff" | decreased
| bgcolor="#dfefff" | none
|-  
|-
| bgcolor="#efefef" | ''CYP2D6*17''
| bgcolor="#efefef" | ''CYP2D6*7''
| bgcolor="#dfefff" | decreased
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*8''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*9''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*10''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*11''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*12''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*13''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*14''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*15''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*17''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*19''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*20''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*21''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*29''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*31''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*38''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*40''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*41''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*42''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*68''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*92''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*100''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*101''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6 duplication''
| bgcolor="#dfefff" | increased
|}
|}


==Ethnic factors in variability==
== Ethnic factors in variability ==
Ethnicity is a factor in the occurrence of CYP2D6 variability. The prevalence of CYP2D6 poor metabolizers is approximately 6-10% amongst [[White people|white]] populations, but is lower in most other ethnic groups such as [[Asian people|Asians]] (2%)<ref>Australian Medicines Handbook (AMH) ''2004. ISBN 0-9578521-4-2''</ref>. In [[Black people|blacks]], the frequency of poor metabolizers is greater than for whites<ref>{{cite journal |author=Gaedigk A, Bradford LD, Marcucci KA, Leeder JS |title=Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans |journal=Clin. Pharmacol. Ther. |volume=72 |issue=1 |pages=76–89 |year=2002 |pmid=12152006 |doi=10.1067/mcp.2002.125783}}</ref>. The occurrence of CYP2D6 ultrarapid metabolisers appears to be greater amongst [[Middle East]]ern and [[North Africa]]n populations<ref>{{cite journal |author=McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M |title=Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians |journal=Pharmacogenetics |volume=7 |issue=3 |pages=187–91 |year=1997 |pmid=9241658 |doi=10.1097/00008571-199706000-00003}}</ref>.
 
Race is a factor in the occurrence of CYP2D6 variability. The lack of the liver cytochrome CYP2D6 enzyme occurs approximately in 7–10% in [[White people|white]] populations, and is lower in most other ethnic groups such as [[Asian people|Asians]] and [[African-Americans]] at 2% each.<ref>{{Cite book|title=Pharmacology and the Nursing Process|last=Lilley, Harrington, Snyder, Swart|first=Linda Lane, Scott, Julie, Beth|publisher=Mosby Elsevier|year=2007|isbn=9780779699711|location=Toronto|pages=25}}</ref> The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among [[Middle East]]ern and [[North Africa]]n populations.<ref name="pmid9241658">{{cite journal | vauthors = McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M | title = Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians | journal = Pharmacogenetics | volume = 7 | issue = 3 | pages = 187–91 | date = June 1997 | pmid = 9241658 | doi = 10.1097/00008571-199706000-00003 }}</ref>
 
Caucasians with European descent predominantly (around 71%) have the functional group of CYP2D6 alleles, while functional alleles represent only around 50% of the allele frequency in populations of Asian descent.<ref name="pmid11972444">{{cite journal | vauthors = Bradford LD | title = CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants | journal = Pharmacogenomics | volume = 3 | issue = 2 | pages = 229–43 | date = March 2002 | pmid = 11972444 | doi = 10.1517/14622416.3.2.229 }}</ref>
 
This variability is accounted for by the differences in the prevalence of various ''CYP2D6'' alleles among the populations–approximately 10% of whites are intermediate metabolizers, due to decreased CYP2D6 function, because they appear to have the non-functional ''CYP2D6*4'' allele,<ref name="Droll_1998">{{cite journal | vauthors = Droll K, Bruce-Mensah K, Otton SV, Gaedigk A, Sellers EM, Tyndale RF | title = Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians | journal = Pharmacogenetics | volume = 8 | issue = 4 | pages = 325–33 | date = August 1998 | pmid = 9731719 | doi = 10.1097/00008571-199808000-00006 }}</ref> while approximately 50% of Asians possess the decreased functioning ''CYP2D6*10'' allele.<ref name="Droll_1998" />
 
== Ligands ==
Following is a table of selected [[enzyme substrate|substrates]], [[enzyme induction and inhibition|inducers]] and [[enzyme induction and inhibition|inhibitors]] of CYP2D6. Where classes of agents are listed, there may be exceptions within the class.


This variability is accounted for by the differences in the prevalence of various ''CYP2D6'' alleles amongst the populations - approximately 10% of whites appear to have the non-functional ''CYP2D6*4'' allele<ref name="pmid9731719">{{cite journal |author=Droll K, Bruce-Mensah K, Otton SV, Gaedigk A, Sellers EM, Tyndale RF |title=Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians |journal=Pharmacogenetics |volume=8 |issue=4 |pages=325–33 |year=1998 |pmid=9731719 |doi=10.1097/00008571-199808000-00006}}</ref> while approximately 50% of Asians possess the ''CYP2D6*10'' allele<ref name="pmid9731719" />, which should produce decreased CYP2D6 function; however this still appears to be within the normal range and are still grouped as extensive metabolisers.
Inhibitors of CYP2D6 can be classified by their [[potency (pharmacology)|potency]], such as:
*'''Strong inhibitor''' being one that causes at least a 5-fold increase in the plasma [[area under the curve (pharmacokinetics)|AUC values]], or more than 80% decrease in [[clearance (medicine)|clearance]].<ref name=Flockhart/>
*'''Moderate inhibitor''' being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.<ref name=Flockhart/>
*'''Weak inhibitor''' being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.<ref name=Flockhart/>


==CYP2D6 [[Ligand (biochemistry)|Ligands]]==
{| class="wikitable" width=100%
{| class="wikitable" width=100%
|+'''Selected inducers, inhibitors and substrates of CYP2D6<ref>Where classes of agents are listed, there may be exceptions within the class</ref>'''
|+'''Selected inducers, inhibitors and substrates of CYP2D6'''
|-
|-
! Substrates !! Inhibitors !! Inducers
! Substrates<br>↑ <small>= [[bioactivation]] by CYP2D6</small> !! Inhibitors !! Inducers
|- style="vertical-align: top;"
|- style="vertical-align: top;"
| '''Often mentioned''': <ref name=importance> Mentioned both in the reference named FASS and were previously mentioned in Wikipedia. Further contributions may follow other systems</ref>  
|<!--substrates-->
* [[beta-blockers]]
* All<ref name=FASS/> [[tricyclic antidepressants]], e.g.
**[[metoprolol]]
** [[imipramine]]<ref name=Flockhart/>
** [[carvedilol]]
** [[amitriptyline]]<ref name=Flockhart/>
** [[timolol]]
* Class I [[antiarrhythmics]]
** [[flecainide]]
** [[lidocaine]]
** [[propafenone]]
** [[encainide]]
** [[mexiletine]]
* All [[tricyclic antidepressants]], e.g.
** [[imipramine]]
** [[amitriptyline]]
** etc.
** etc.
* Most [[SSRI]]s, e.g.
* Most<ref name=FASS/> [[SSRI]]s (antidepressant), e.g.
** [[fluoxetine]]
** [[fluoxetine]]<ref name=Flockhart/>
** [[paroxetine]]
** [[paroxetine]]<ref name=Flockhart/>
** [[fluvoxamine]]<ref name=Flockhart/>
* [[venlafaxine]]<ref name=Flockhart/><ref name=FASS/> ([[serotonin-norepinephrine reuptake inhibitor|SNRI]] antidepressant)
* [[duloxetine]]<ref name=Flockhart/> ([[serotonin-norepinephrine reuptake inhibitor|SNRI]])
* [[mianserin]]<ref name=FASS/> ([[tetracyclic antidepressant]])
* [[mirtazapine]]<ref name=FASS/> ([[antidepressant]])
* [[opioids]]
* [[opioids]]
** [[codeine]]
** [[codeine]]<ref name=Flockhart/><ref name=FASS/> [[bioactivation|&uarr;]][into [[morphine]]]<ref name=Leeder>{{cite journal | vauthors = Leeder JS | title = Pharmacogenetics and pharmacogenomics | journal = Pediatric Clinics of North America | volume = 48 | issue = 3 | pages = 765–81 | date = June 2001 | pmid = 11411304 | doi = 10.1016/S0031-3955(05)70338-2 }}</ref>
** [[tramadol]]
** [[tramadol]]<ref name=Flockhart/><ref name=FASS/> [[bioactivation|&uarr;]][into [[O-desmethyltramadol]]]<ref name=Leeder/>
* [[debrisoquine]] ([[antihypertensive]])
** [[O-desmethyltramadol]] [[bioactivation|&uarr;]][into N,O-didesmethyltramadol]
* [[dextromethorphan]] ([[antitussive]])
** [[N-desmethyltramadol]] [inactive] [[bioactivation|&uarr;]][into N,O-didesmethyltramadol]
* [[venlafaxine]] ([[serotonin-norepinephrine reuptake inhibitor|SNRI]])
** [[oxycodone]]<ref name=Flockhart/>
** [[hydrocodone]] [[bioactivation|&uarr;]][into [[hydromorphone]]]<ref>{{cite web |url= http://www.drugbank.ca/drugs/DB00956 |title= Hydrocodone |publisher= Drugbank |accessdate=14 June 2011}}</ref>
** [[tapentadol]]
* [[antipsychotics]], e.g.
* [[antipsychotics]], e.g.
** [[haloperidol]]
** [[haloperidol]]<ref name=Flockhart/><ref name=FASS/>
** [[risperidone]]
** [[risperidone]]<ref name=Flockhart/><ref name=FASS/>
** [[perphenazine]]
** [[perphenazine]]<ref name=Flockhart/><ref name=FASS/>
** [[thioridazine]]
** [[thioridazine]]<ref name=Flockhart/><ref name=FASS/>
** [[zuclopenthixol]]
** [[zuclopenthixol]]<ref name=Flockhart/><ref name=FASS/>
** [[remoxipride]]
** [[iloperidone]]<ref name=Flockhart/><ref name=FASS/>
** [[aripiprazole]]
** [[aripiprazole]]<ref name=Flockhart/><ref name=FASS/>
* [[ondansetron]] ([[5-HT3 receptor antagonist]])
** [[chlorpromazine]]<ref name=Flockhart/><ref name=FASS/>
** [[levomepromazine]]<ref name=FASS/>
** [[remoxipride]]<ref name=FASS/>
* [[minaprine]]<ref name=Flockhart/> ([[reversible inhibitor of MAO-A|RIMA]] antidepressant)
* [[tamoxifen]]<ref name=Flockhart/><ref name=FASS/> [[bioactivation|&uarr;]][into [[hydroxytamoxifen]]]<ref name="pmid19629072">{{cite journal | vauthors = Hoskins JM, Carey LA, McLeod HL | title = CYP2D6 and tamoxifen: DNA matters in breast cancer | journal = Nature Reviews. Cancer | volume = 9 | issue = 8 | pages = 576–86 | date = August 2009 | pmid = 19629072 | doi = 10.1038/nrc2683 }}</ref> ([[selective estrogen receptor modulator|SERM]])
* [[beta-blockers]]
** [[metoprolol]]<ref name=Flockhart/><ref name=FASS/>
** [[timolol]]<ref name=Flockhart/><ref name=FASS/>
** [[alprenolol]]<ref name=Flockhart/><ref name=FASS/>
** [[carvedilol]]<ref name=Flockhart/>
** [[bufuralol]]<ref name=Flockhart/>
** [[nebivolol]]<ref name=Flockhart/>
** [[propranolol]]<ref name=Flockhart/>
* [[debrisoquine]]<ref name=Flockhart/> ([[antihypertensive]])
* Class I [[antiarrhythmics]]
** [[flecainide]]<ref name=Flockhart/><ref name=FASS/>
** [[propafenone]]<ref name=Flockhart/><ref name=FASS/>
** [[encainide]]<ref name=Flockhart/><ref name=FASS/>
** [[mexiletine]]<ref name=Flockhart/><ref name=FASS/>
** [[lidocaine]] (mainly by 3A4)<ref name=Flockhart/>
** [[sparteine]]<ref name=Flockhart/>
* [[ondansetron]]<ref name=Flockhart/><ref name=FASS/> ([[antiemetic]])
* [[donepezil]]<ref name=Flockhart/><ref name=FASS/> ([[acetylcholinesterase inhibitor]])
* [[phenformin]]<ref name=Flockhart/><ref name=FASS/> ([[antidiabetic]])
* [[tropisetron]]<ref name=FASS/> ([[5-HT3 receptor antagonist]])
* [[stimulants]]
** [[amphetamine]]<ref name=Flockhart/>
** [[methoxyamphetamine]]<ref name=Flockhart/>
** [[dextromethamphetamine]]<ref name=Flockhart/>
* [[atomoxetine]]<ref name=Flockhart/>
* [[chlorphenamine]]<ref name=Flockhart/> ([[antihistamine]])
* [[dexfenfluramine]]<ref name=Flockhart/> ([[serotonin]]ergic [[anorectic]])
* [[dextromethorphan]]<ref name=Flockhart/> [[bioactivation|&uarr;]][into [[dextrorphan]]] ([[antitussive]])
* [[metoclopramide]]<ref name=Flockhart/> ([[dopamine antagonist]])
* [[perhexiline]]<ref name=Flockhart/> ([[antianginal agent]])
* [[phenacetin]]<ref name=Flockhart/> ([[analgesic]])
* [[promethazine]]<ref name=Flockhart/> ([[antihistamine]] [[antiemetic]])
* [[m-tyramine|''m''-tyramine]]<ref name="CYP2D6 tyramine-dopamine metabolism" />
* [[p-tyramine|''p''-tyramine]]<ref name="CYP2D6 tyramine-dopamine metabolism" />
||


'''Other''':
'''Strong'''<!--inhibitors-->
* [[alprenolol]] ([[beta-blocker]])
* Certain [[Selective serotonin reuptake inhibitor|SSRI]]s
* [[atenolol]] ([[beta-blocker]])
** [[fluoxetine]]<ref name=Flockhart/><ref name=FASS>[[FASS (drug formulary)]]: [http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 Swedish environmental classification of pharmaceuticals] Facts for prescribers (Fakta för förskrivare), retrieved July 2011</ref>
* [[mianserin]] ([[tetracyclic antidepressant]])
** [[paroxetine]]<ref name=Flockhart/><ref name=FASS/>
* [[phenformin]] ([[antidiabetic]])
* [[bupropion]]<ref name=Flockhart/><ref name="pmid15876900">{{cite journal | vauthors = Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, Adson DE | title = Inhibition of CYP2D6 activity by bupropion | journal = Journal of Clinical Psychopharmacology | volume = 25 | issue = 3 | pages = 226–9 | date = June 2005 | pmid = 15876900 | doi = 10.1097/01.jcp.0000162805.46453.e3 }}</ref> (non-SSRI antidepressant)
* [[tropisetron]] ([[5-HT3 receptor antagonist]])
* [[quinidine]]<ref name=Flockhart/><ref name=FASS/> ([[class I antiarrhythmic agent]])
* [[amphetamine]] (in [[Attention-deficit hyperactivity disorder|ADHD]], [[narcolepsy]])
* [[quinine]]<ref>{{cite journal | vauthors = Fasinu PS, Tekwani BL, Avula B, Chaurasiya ND, Nanayakkara NP, Wang YH, Khan IA, Walker LA | title = Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine | journal = Malaria Journal | volume = 15 | pages = 466 | date = September 2016 | pmid = 27618912 | doi = 10.1186/s12936-016-1509-x | pmc=5020452}}</ref>
* [[chlorphenamine]] ([[antihistamine]])
* [[cinacalcet]]<ref name=Flockhart/> (calcimimetic)
* [[metoclopramide]] ([[dopamine antagonist]])
* [[ritonavir]]<ref name=FASS/> ([[antiretroviral]])
* [[tamoxifen]] ([[selective estrogen receptor modulator|SERM]])
* [[vinca alkaloid]]s ([[anti-mitotic]], anti-[[microtubule]])
** [[vincristine]]


|| '''Strong''': <ref name=FASS>[http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 Swedish environmental classification of pharmaceuticals] Facts for prescribers (Fakta för förskrivare)</ref>  
'''Moderate'''<!--inhibitors-->
* [[Selective serotonin reuptake inhibitor|SSRI]]s
* [[sertraline]]<ref name=Flockhart/> ([[Selective serotonin reuptake inhibitor|SSRI]])
** [[citalopram]]
* [[duloxetine]]<ref name=Flockhart/> ([[serotonin-norepinephrine reuptake inhibitor|SNRI]])
** [[fluoxetine]]
* [[terbinafine]]<ref name=Flockhart/> ([[Antifungal medication|antifungal]])
** [[paroxetine]]
* [[bupropion]] ([[antidepressant]])
* [[duloxetine]] ([[anti-depressant]])
* [[terbinafine]] ([[antifungal]])
* [[quinidine]] ([[class I antiarrhythmic agent]])


'''unspecified''':
'''Weak'''<!--inhibitors-->
* [[amiodarone]] ([[antiarrhythmic]])
* [[amiodarone]]<ref name=Flockhart>{{cite web |author=Flockhart DA |title=Drug Interactions: Cytochrome P<sub>450</sub> Drug Interaction Table |publisher=[[Indiana University School of Medicine]] |year=2007 |url=http://medicine.iupui.edu/flockhart/table.htm}} Retrieved in July 2011</ref> ([[antiarrhythmic]])
* [[antihistamine]] ([[H1-receptor antagonists]])
* [[buprenorphine]]<ref name="pmid12756210">{{cite journal | vauthors = Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM | title = Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro | journal = Drug Metabolism and Disposition | volume = 31 | issue = 6 | pages = 768–72 | date = June 2003 | pmid = 12756210 | doi = 10.1124/dmd.31.6.768 }}</ref> (in opioid addiction)
** [[chlorphenamine]]
* [[cimetidine]]<ref name=Flockhart/> ([[H2-receptor antagonist]])
** [[diphenhydramine]]
* [[citalopram]]<ref name=Flockhart/><ref name = "drugs.com">{{cite web | url = https://www.drugs.com/pro/citalopram-oral-solution.html|title = Citalopram Oral Solution | work = Drugs.com }}</ref> ([[Selective serotonin reuptake inhibitor|SSRI]])
* [[antipsychotic]]
* [[escitalopram]]<ref name=Flockhart/<ref name = "drugs.com" /> ([[Selective serotonin reuptake inhibitor|SSRI]])
** [[chlorpromazine]]
* [[methylphenidate]] <ref>{{cite journal | url = http://www.gjpsy.uni-goettingen.de/gjp-article-nevels.pdf | title = Methylphenidate and Its Under-recognized, Under- explained, and Serious Drug Interactions: A Review of the Literature with Heightened Concerns | journal = German Journal of Psychiatry | date = July 2013 | pages = 29–42 | vauthors = Nevels RM, Weiss NH, Killebrew AE, Gontkovsky ST }}</ref>
** [[haloperidol]]
* [[celecoxib]] ([[NSAID]])
* [[cimetidine]] ([[H2-receptor antagonist]])
* [[clomipramine]] ([[tricyclic antidepressant]])
* [[chloramphenicol]] ([[laevomycetin]])
* [[cocaine]] ([[stimulant]])
* [[doxorubicin]] ([[chemotherapeutic]])
* [[metoclopramide]] ([[antiemetic]], [[prokinetic]])
* [[methadone]] ([[analgesic]] and [[anti-addictive]])
* [[moclobemide]] ([[antidepressant]])
* [[quinidine]] ([[Class I antiarrhythmic agent|Class I antiarrhythmic]])
* [[ranitidine]] ([[H2-receptor antagonist]])
* [[ranolazine]] ([[antianginal]])
* [[ritonavir]] ([[antiretroviral]])
* [[doxepin]] ([[tricyclic antidepressant]], [[anxiolytic]])
* [[halofantrine]] (in [[malaria]])
* [[imipramine]] ([[tricyclic antidepressant]])
* [[levomepromazine]] ([[antipsychotic]])
* [[metoclopramide]] ([[antiemetic]], [[prokinetic]])
* [[pimozide]] ([[antipsychotic]])
* [[thioridazine]] ([[antipsychotic]])


'''<!--inhibitors of-->Unspecified potency'''
* [[antipsychotic]]s
** [[haloperidol]]<ref name=fass-codeine>[[FASS (drug formulary)|FASS]], [http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=19731109000032&DocTypeID=6 The Swedish official drug catalog > Kodein Recip] Last reviewed 2008-04-08</ref><ref name=Flockhart/>
** [[perphenazine]]<ref name=Flockhart/><ref name=fass-codeine/>
** [[thioridazine]]<ref name=fass-codeine/>
** [[zuclopenthixol]]<ref name=fass-codeine/>
** [[chlorpromazine]]<ref name=Flockhart/>
* [[hyperforin]] ([[St. Johns Wort]])<ref>{{cite journal |doi=10.1080/13880200490512034 |title=''In Vitro'' Activity of St. John's Wort Against Cytochrome P450 Isozymes and P-Glycoprotein |journal=Pharmaceutical Biology |volume=42 |issue=2 |pages=159–69 |year=2008 |last1=Foster |first1=B.C |last2=Sockovie |first2=E.R |last3=Vandenhoek |first3=S |last4=Bellefeuille |first4=N |last5=Drouin |first5=C.E |last6=Krantis |first6=A |last7=Budzinski |first7=J.W |last8=Livesey |first8=J |last9=Arnason |first9=J.T }}</ref>
* [[antihistamine]]s ([[H1-receptor antagonists]])
** [[promethazine]]<ref name="pmid11936702">{{cite journal | vauthors = He N, Zhang WQ, Shockley D, Edeki T | title = Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes | journal = European Journal of Clinical Pharmacology | volume = 57 | issue = 12 | pages = 847–51 | date = February 2002 | pmid = 11936702 | doi = 10.1007/s00228-001-0399-0 }}</ref> ([[sedative|antipsychotic]])
** [[chlorphenamine]]<ref name=Flockhart/>
** [[diphenhydramine]]<ref name=Flockhart/>
** [[hydroxyzine]]<ref name=Flockhart/>
** [[tripelennamine]]<ref name=Flockhart/>
* [[clemastine]]<ref name=Flockhart/> ([[antihistamine]] and [[anticholinergic]])
* [[celecoxib]]<ref name=Flockhart/> ([[NSAID]])
* [[clomipramine]]<ref name=Flockhart/> ([[tricyclic antidepressant]])
* [[cocaine]]<ref name=Flockhart/> ([[stimulant]])
* [[doxorubicin]]<ref name=Flockhart/> ([[chemotherapeutic]])
* [[metoclopramide]]<ref name=Flockhart/> ([[antiemetic]], [[prokinetic]])
* [[methadone]]<ref name=Flockhart/> ([[analgesic]] and [[anti-addictive]])
* [[moclobemide]]<ref name=Flockhart/> ([[antidepressant]])
* [[niacin]]<ref name = "Gaudineau_2004">{{cite journal | vauthors = Gaudineau C, Auclair K | title = Inhibition of human P450 enzymes by nicotinic acid and nicotinamide | journal = Biochemical and Biophysical Research Communications | volume = 317 | issue = 3 | pages = 950–6 | date = May 2004 | pmid = 15081432 | doi = 10.1016/j.bbrc.2004.03.137 }}</ref> ([[vitamin]])
* [[nicotinamide]]<ref name = "Gaudineau_2004" /> ([[vitamin]])
* [[doxepin]]<ref name=Flockhart/> ([[tricyclic antidepressant]], [[anxiolytic]])
* [[halofantrine]]<ref name=Flockhart/> (in [[malaria]])
* [[levomepromazine]]<ref name=Flockhart/> ([[antipsychotic]])
* [[mibefradil]]<ref name=Flockhart/> ([[calcium channel blocker]])
* [[midodrine]]<ref name=Flockhart/> ([[Alpha-1 adrenergic agonist|α<sub>1</sub> agonist]])
* [[ticlopidine]]<ref name=Flockhart/> ([[antiplatelet drug|antiplatelet]])
* [[cannabidiol]]<ref name="pmid21821735">{{cite journal | vauthors = Yamaori S, Okamoto Y, Yamamoto I, Watanabe K | title = Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6 | journal = Drug Metabolism and Disposition | volume = 39 | issue = 11 | pages = 2049–56 | date = November 2011 | pmid = 21821735 | doi = 10.1124/dmd.111.041384 }}</ref> ([[phytocannabinoid]])
||
||
'''Strong:'''
* [[Piperidine]]s and derivatives ([[pharmacokinetics]] modifiers)
**[[glutethimide]] ([[piperidinedione]] derivative) 
'''"Half"-Strong''':
* [[carbamazepine]]
'''Unspecified''':
* [[dexamethasone]] ([[glucocorticoid]])
* [[rifampicin]] ([[bactericidal]])


'''Strong'''<!--inducers-->
* [[glutethimide]]<!-- <ref name=Dave/> --> ([[hypnotic|hypnotic sedative]])
'''<!--inducers of-->Unspecified potency'''
* [[dexamethasone]]<ref name=Flockhart/> ([[glucocorticoid]])
* [[rifampicin]]<ref name=Flockhart/> ([[bactericidal]])
* [[haloperidol]]<ref>{{cite journal | vauthors = Kudo S, Ishizaki T | title = Pharmacokinetics of haloperidol: an update | journal = Clinical Pharmacokinetics | volume = 37 | issue = 6 | pages = 435–56 | date = December 1999 | pmid = 10628896 | doi = 10.2165/00003088-199937060-00001 }}</ref> ([[typical antipsychotic]])
|-
|-
|}
|}


==References==
===Dopamine biosynthesis===
{{reflist}}
{{Catecholamine and trace amine biosynthesis|caption=In humans, [[catecholamine]]s and phenethylaminergic [[trace amine]]s are derived from the amino acid [[phenylalanine]]. It is well established that dopamine is produced from L-tyrosine via L-dopa; however, recent evidence has shown that CYP2D6 is expressed in the human brain and catalyzes the biosynthesis of dopamine from L-tyrosine via ''p''-tyramine.<ref name="CYP2D6 tyramine-dopamine metabolism" /> Similarly, CYP2D6 also metabolizes [[m-tyramine|''m''-tyramine]] into dopamine.<ref name="CYP2D6 tyramine-dopamine metabolism" />}}
 
== References ==
{{reflist|colwidth=35em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|colwidth=35em}}
{{PBB_Further_reading
* {{cite journal | vauthors = Smith G, Stubbins MJ, Harries LW, Wolf CR | title = Molecular genetics of the human cytochrome P450 monooxygenase superfamily | journal = Xenobiotica | volume = 28 | issue = 12 | pages = 1129–65 | date = December 1998 | pmid = 9890157 | doi = 10.1080/004982598238868 }}
| citations =
* {{cite journal | vauthors = Wolf CR, Smith G | title = Cytochrome P450 CYP2D6 | journal = IARC Scientific Publications | issue = 148 | pages = 209–29 | year = 1999 | pmid = 10493260 }}
*{{cite journal | author=Smith G, Stubbins MJ, Harries LW, Wolf CR |title=Molecular genetics of the human cytochrome P450 monooxygenase superfamily |journal=Xenobiotica |volume=28 |issue= 12 |pages= 1129–65 |year= 1999 |pmid= 9890157 |doi= }}
* {{cite journal | vauthors = Ding X, Kaminsky LS | title = Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts | journal = Annual Review of Pharmacology and Toxicology | volume = 43 | pages = 149–73 | year = 2003 | pmid = 12171978 | doi = 10.1146/annurev.pharmtox.43.100901.140251 }}
*{{cite journal | author=Wolf CR, Smith G |title=Cytochrome P450 CYP2D6 |journal=IARC Sci. Publ. |volume= |issue= 148 |pages= 209–29 |year= 1999 |pmid= 10493260 |doi=  }}
* {{cite journal | vauthors = Lilienfeld S | title = Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease | journal = CNS Drug Reviews | volume = 8 | issue = 2 | pages = 159–76 | year = 2006 | pmid = 12177686 | doi = 10.1111/j.1527-3458.2002.tb00221.x }}
*{{cite journal | author=Ding X, Kaminsky LS |title=Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts |journal=Annu. Rev. Pharmacol. Toxicol. |volume=43 |issue=  |pages= 149–73 |year= 2003 |pmid= 12171978 |doi= 10.1146/annurev.pharmtox.43.100901.140251 }}
* {{cite journal | vauthors = Yu AM, Idle JR, Gonzalez FJ | title = Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates | journal = Drug Metabolism Reviews | volume = 36 | issue = 2 | pages = 243–77 | date = May 2004 | pmid = 15237854 | doi = 10.1081/DMR-120034000 }}
*{{cite journal | author=Lilienfeld S |title=Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease |journal=CNS drug reviews |volume=8 |issue= 2 |pages= 159–76 |year= 2002 |pmid= 12177686 |doi= }}
* {{cite journal | vauthors = Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, Luccarini C, Shah M, Ingle S, Greenberg D, Earl HM, Dunning AM, Pharoah PD, Caldas C | title = CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen | journal = Breast Cancer Research | volume = 12 | issue = 4 | pages = R64 | year = 2010 | pmid = 20731819 | pmc = 2949659 | doi = 10.1186/bcr2629 }}
*{{cite journal | author=Yu AM, Idle JR, Gonzalez FJ |title=Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates |journal=Drug Metab. Rev. |volume=36 |issue= 2 |pages= 243–77 |year= 2004 |pmid= 15237854 |doi= 10.1081/DMR-120034000}}
* {{cite journal | vauthors = Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, Luccarini C, Earl HM, Dunning AM, Pharoah PD, Caldas C | title = CYP2D6 gene variants and their association with breast cancer susceptibility | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 20 | issue = 6 | pages = 1255–8 | date = June 2011 | pmid = 21527579 | doi = 10.1158/1055-9965.EPI-11-0321 }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
*[http://medicine.iupui.edu/flockhart/2D6.htm#2D6sub Flockhart Lab Cyp2D6 Substrates Page] at [[Indiana University-Purdue University Indianapolis|IUPUI]]
* [http://medicine.iupui.edu/flockhart/2D6.htm#2D6sub Flockhart Lab Cyp2D6 Substrates Page] at [[Indiana University-Purdue University Indianapolis|IUPUI]]
* [https://web.archive.org/web/20081207081045/http://www.pharmgkb.org/search/annotatedGene/cyp2d6/index.jsp PharmGKB: Annotated PGx Gene Information for CYP2D6]
* {{UCSC gene info|CYP2D6}}


{{Oxygenases}}
{{PDB Gallery|geneid=1565}}
{{Cytochrome P450}}
{{Cytochrome P450}}
{{SIB}}
{{Dioxygenases}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}


[[Category:Cytochrome P450]]
[[Category:Cytochrome P450]]
[[Category:EC 1.14.14]]
[[Category:EC 1.14.14]]
 
[[Category:Amphetamine]]
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Latest revision as of 12:22, 9 January 2019

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Orthologs
SpeciesHumanMouse
Entrez

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View/Edit Human

Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. CYP2D6 is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.

CYP2D6, a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. In particular, CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, via the addition or removal of certain functional groups – specifically, hydroxylation, demethylation, and dealkylation.[1] Other drugs, known as prodrugs, are activated by the action of CYP2D6. This enzyme also metabolizes several endogenous substances, such as hydroxytryptamines, neurosteroids, and both m-tyramine and p-tyramine which CYP2D6 metabolizes into dopamine in the brain and liver.[1][2]

Considerable variation exists in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence, for drugs that are metabolized by CYP2D6 (that is, are CYP2D6 substrates), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers). If a drug is metabolized too quickly, it may decrease the drug's efficacy while if the drug is metabolized too slowly, toxicity may result.[3] So, the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6.[4]

Other drugs may function as inhibitors of CYP2D6 activity or inducers of CYP2D6 enzyme expression that will lead to decreased or increased CYP2D6 activity respectively. If such a drug is taken at the same time as a second drug that is a CYP2D6 substrate, the first drug may affect the elimination rate of the second through what is known as a drug-drug interaction.[3]

Gene

The gene is located near two cytochrome P450 pseudogenes on chromosome 22q13.1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[5]

Genotype/phenotype variability

CYP2D6 shows the largest phenotypical variability among the CYPs, largely due to genetic polymorphism. The genotype accounts for normal, reduced, and non-existent CYP2D6 function in subjects. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice.[6] The CYP2D6 function in any particular subject may be described as one of the following:[7]

  • poor metabolizer – little or no CYP2D6 function
  • intermediate metabolizers – metabolize drugs at a rate somewhere between the poor and extensive metabolizers
  • extensive metabolizer – normal CYP2D6 function
  • ultrarapid metabolizer – multiple copies of the CYP2D6 gene are expressed, so greater-than-normal CYP2D6 function occurs

A patient's CYP2D6 phenotype is often clinically determined via the administration of debrisoquine (a selective CYP2D6 substrate) and subsequent plasma concentration assay of the debrisoquine metabolite (4-hydroxydebrisoquine).[8]

The type of CYP2D6 function of an individual may influence the person's response to different doses of drugs that CYP2D6 metabolizes. The nature of the effect on the drug response depends not only on the type of CYP2D6 function, but also on the extent to which processing of the drug by CYP2D6 results in a chemical that has an effect that is similar, stronger, or weaker than the original drug, or no effect at all. For example, if CYP2D6 converts a drug that has a strong effect into a substance that has a weaker effect, then poor metabolizers (weak CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects; conversely, if CYP2D6 converts a different drug into a substance that has a greater effect than its parent chemical, then ultrarapid metabolizers (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects.[9]

Genetic basis of variability

The genetic basis for CYP2D6-mediated metabolic variability is the CYP2D6 allele, located on chromosome 22. Subjects possessing certain allelic variants will show normal, decreased, or no CYP2D6 function, depending on the allele. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice.[6]

CYP2D6 enzyme activity for selected alles[10][11]
Allele CYP2D6 activity
CYP2D6*1 normal
CYP2D6*2 normal
CYP2D6*3 none
CYP2D6*4 none
CYP2D6*5 none
CYP2D6*6 none
CYP2D6*7 none
CYP2D6*8 none
CYP2D6*9 decreased
CYP2D6*10 decreased
CYP2D6*11 none
CYP2D6*12 none
CYP2D6*13 none
CYP2D6*14 none
CYP2D6*15 none
CYP2D6*17 decreased
CYP2D6*19 none
CYP2D6*20 none
CYP2D6*21 none
CYP2D6*29 decreased
CYP2D6*31 none
CYP2D6*38 none
CYP2D6*40 none
CYP2D6*41 decreased
CYP2D6*42 none
CYP2D6*68 none
CYP2D6*92 none
CYP2D6*100 none
CYP2D6*101 none
CYP2D6 duplication increased

Ethnic factors in variability

Race is a factor in the occurrence of CYP2D6 variability. The lack of the liver cytochrome CYP2D6 enzyme occurs approximately in 7–10% in white populations, and is lower in most other ethnic groups such as Asians and African-Americans at 2% each.[12] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.[13]

Caucasians with European descent predominantly (around 71%) have the functional group of CYP2D6 alleles, while functional alleles represent only around 50% of the allele frequency in populations of Asian descent.[14]

This variability is accounted for by the differences in the prevalence of various CYP2D6 alleles among the populations–approximately 10% of whites are intermediate metabolizers, due to decreased CYP2D6 function, because they appear to have the non-functional CYP2D6*4 allele,[10] while approximately 50% of Asians possess the decreased functioning CYP2D6*10 allele.[10]

Ligands

Following is a table of selected substrates, inducers and inhibitors of CYP2D6. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2D6 can be classified by their potency, such as:

  • Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.[15]
  • Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.[15]
  • Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.[15]
Selected inducers, inhibitors and substrates of CYP2D6
Substrates
↑ = bioactivation by CYP2D6		 Inhibitors Inducers

Strong

Moderate

Weak

Unspecified potency

Strong

Unspecified potency

Dopamine biosynthesis

Biosynthetic pathways for catecholamines and trace amines in the human brain[32][33][20]
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine. It is well established that dopamine is produced from L-tyrosine via L-dopa; however, recent evidence has shown that CYP2D6 is expressed in the human brain and catalyzes the biosynthesis of dopamine from L-tyrosine via p-tyramine.[20] Similarly, CYP2D6 also metabolizes m-tyramine into dopamine.[20]

References

  1. ↑ 1.0 1.1 Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF (2009). "New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme". Drug Metabolism Reviews. 41 (4): 573–643. doi:10.1080/03602530903118729. PMID 19645588.
  2. ↑ Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". European Journal of Pharmacology. 724: 211–8. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199.
  3. ↑ 3.0 3.1 Teh LK, Bertilsson L (2012). "Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance". Drug Metabolism and Pharmacokinetics. 27 (1): 55–67. doi:10.2133/dmpk.DMPK-11-RV-121. PMID 22185816.
  4. ↑ Walko CM, McLeod H (April 2012). "Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment". Pharmacogenomics. 13 (6): 691–7. doi:10.2217/pgs.12.27. PMID 22515611.
  5. ↑ "Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6".
  6. ↑ 6.0 6.1 Dinama O, Warren AM, Kulkarni J (August 2014). "The role of pharmacogenomic testing in psychiatry: Real world examples". The Australian and New Zealand Journal of Psychiatry. 48 (8): 778. doi:10.1177/0004867413520050. PMID 24413808.
  7. ↑ Bertilsson L, Dahl ML, Dalén P, Al-Shurbaji A (February 2002). "Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs". British Journal of Clinical Pharmacology. 53 (2): 111–22. doi:10.1046/j.0306-5251.2001.01548.x. PMC 1874287. PMID 11851634.
  8. ↑ Llerena A, Dorado P, Peñas-Lledó EM (January 2009). "Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity". Pharmacogenomics. 10 (1): 17–28. doi:10.2217/14622416.10.1.17. PMID 19102711.
  9. ↑ Lynch T, Price A (August 2007). "The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects". American Family Physician. 76 (3): 391–6. PMID 17708140.
  10. ↑ 10.0 10.1 10.2 Droll K, Bruce-Mensah K, Otton SV, Gaedigk A, Sellers EM, Tyndale RF (August 1998). "Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians". Pharmacogenetics. 8 (4): 325–33. doi:10.1097/00008571-199808000-00006. PMID 9731719.
  11. ↑ "CYP2D6 allele nomenclature". Retrieved 5 February 2016.
  12. ↑ Lilley, Harrington, Snyder, Swart, Linda Lane, Scott, Julie, Beth (2007). Pharmacology and the Nursing Process. Toronto: Mosby Elsevier. p. 25. ISBN 9780779699711.
  13. ↑ McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M (June 1997). "Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians". Pharmacogenetics. 7 (3): 187–91. doi:10.1097/00008571-199706000-00003. PMID 9241658.
  14. ↑ Bradford LD (March 2002). "CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants". Pharmacogenomics. 3 (2): 229–43. doi:10.1517/14622416.3.2.229. PMID 11972444.
  15. ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 15.11 15.12 15.13 15.14 15.15 15.16 15.17 15.18 15.19 15.20 15.21 15.22 15.23 15.24 15.25 15.26 15.27 15.28 15.29 15.30 15.31 15.32 15.33 15.34 15.35 15.36 15.37 15.38 15.39 15.40 15.41 15.42 15.43 15.44 15.45 15.46 15.47 15.48 15.49 15.50 15.51 15.52 15.53 15.54 15.55 15.56 15.57 15.58 15.59 15.60 15.61 15.62 15.63 15.64 15.65 15.66 15.67 15.68 15.69 15.70 15.71 15.72 15.73 15.74 15.75 15.76 15.77 15.78 15.79 15.80 15.81 15.82 15.83 15.84 Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. Retrieved in July 2011
  16. ↑ 16.00 16.01 16.02 16.03 16.04 16.05 16.06 16.07 16.08 16.09 16.10 16.11 16.12 16.13 16.14 16.15 16.16 16.17 16.18 16.19 16.20 16.21 16.22 16.23 16.24 16.25 16.26 16.27 16.28 16.29 16.30 16.31 16.32 FASS (drug formulary): Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare), retrieved July 2011
  17. ↑ 17.0 17.1 Leeder JS (June 2001). "Pharmacogenetics and pharmacogenomics". Pediatric Clinics of North America. 48 (3): 765–81. doi:10.1016/S0031-3955(05)70338-2. PMID 11411304.
  18. ↑ "Hydrocodone". Drugbank. Retrieved 14 June 2011.
  19. ↑ Hoskins JM, Carey LA, McLeod HL (August 2009). "CYP2D6 and tamoxifen: DNA matters in breast cancer". Nature Reviews. Cancer. 9 (8): 576–86. doi:10.1038/nrc2683. PMID 19629072.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199.
  21. ↑ Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, Adson DE (June 2005). "Inhibition of CYP2D6 activity by bupropion". Journal of Clinical Psychopharmacology. 25 (3): 226–9. doi:10.1097/01.jcp.0000162805.46453.e3. PMID 15876900.
  22. ↑ Fasinu PS, Tekwani BL, Avula B, Chaurasiya ND, Nanayakkara NP, Wang YH, Khan IA, Walker LA (September 2016). "Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine". Malaria Journal. 15: 466. doi:10.1186/s12936-016-1509-x. PMC 5020452. PMID 27618912.
  23. ↑ Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro". Drug Metabolism and Disposition. 31 (6): 768–72. doi:10.1124/dmd.31.6.768. PMID 12756210.
  24. ↑ 24.0 24.1 "Citalopram Oral Solution". Drugs.com.
  25. ↑ Nevels RM, Weiss NH, Killebrew AE, Gontkovsky ST (July 2013). "Methylphenidate and Its Under-recognized, Under- explained, and Serious Drug Interactions: A Review of the Literature with Heightened Concerns" (PDF). German Journal of Psychiatry: 29–42.
  26. ↑ 26.0 26.1 26.2 26.3 FASS, The Swedish official drug catalog > Kodein Recip Last reviewed 2008-04-08
  27. ↑ Foster, B.C; Sockovie, E.R; Vandenhoek, S; Bellefeuille, N; Drouin, C.E; Krantis, A; Budzinski, J.W; Livesey, J; Arnason, J.T (2008). "In Vitro Activity of St. John's Wort Against Cytochrome P450 Isozymes and P-Glycoprotein". Pharmaceutical Biology. 42 (2): 159–69. doi:10.1080/13880200490512034.
  28. ↑ He N, Zhang WQ, Shockley D, Edeki T (February 2002). "Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes". European Journal of Clinical Pharmacology. 57 (12): 847–51. doi:10.1007/s00228-001-0399-0. PMID 11936702.
  29. ↑ 29.0 29.1 Gaudineau C, Auclair K (May 2004). "Inhibition of human P450 enzymes by nicotinic acid and nicotinamide". Biochemical and Biophysical Research Communications. 317 (3): 950–6. doi:10.1016/j.bbrc.2004.03.137. PMID 15081432.
  30. ↑ Yamaori S, Okamoto Y, Yamamoto I, Watanabe K (November 2011). "Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6". Drug Metabolism and Disposition. 39 (11): 2049–56. doi:10.1124/dmd.111.041384. PMID 21821735.
  31. ↑ Kudo S, Ishizaki T (December 1999). "Pharmacokinetics of haloperidol: an update". Clinical Pharmacokinetics. 37 (6): 435–56. doi:10.2165/00003088-199937060-00001. PMID 10628896.
  32. ↑ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.
  33. ↑ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375.

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