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CYP2D6 Metabolizing enzyme

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CYP2D6 Metabolizing enzyme

8.3.2. CYP2D6

CYP2D6 metabolizes about 25% of all drug substances, including drugs relevant to the treatment of ADHD

  • Elvanse (AMP)
  • Atomoxetine
  • Nortryptiline
  • Imipramine
  • Desipramine (now irrelevant, strong inhibitor)

A CYP2D6 gene defect is inherited in an autosomal recessive manner.
Based on experience with the influence of CYP2D6 on the effects of other drugs (CYP2D6 is responsible for the metabolization of 20 to 30% of all drugs), the different CYP2D6 gene variants result in different types of metabolism1

  • Approximately 90%2 of Europeans carry the wild type or a heterozygous defect
    • Moderately fast metabolizers - approx. 40 %1
    • Fast metabolizer - approx. 46 %1
    • CYP2D6 is fully efficient
    • Carriers are “extensive metabolizers (EM)”
  • Approximately 7%1 to just under 10%2 of Europeans carry a homozygous enzyme defect
    • CYP2D6 has limited capacity
    • Carriers are poor metabolizers (PM)
      • Effects amplified
      • Increased risk of side effects
      • Especially slow dosing important
      • Special low dosage helpful
  • In contrast, approximately 1.5%3 to 7%1 of Europeans have up to 12 active CYP2D6 copies
    • CYP2D6 is hyper-performing
    • Carriers are “ultra-rapid metabolizers”
      • Accelerated degradation of drugs
        • May lead to ineffectiveness
        • Especially for drugs with a high first-pass effect
        • Is associated with therapy resistance (non-responders)
        • Increased dose / more frequent dosing may be helpful

A more general distinction of metabolization types is:24

  • Slow metabolizer (PM)
    • No wild-type allele present (homozygous mutant); both alleles inactive, insufficient amount of functional enzyme
  • Intermediate Metabolizer (IM)
    • At least 1 wild-type allele retained (heterozygous); 1 allele active and 1 allele inactive or impaired active or both alleles impaired active, reduced functional enzyme
  • Extensive Metabolizer (EM)
    • At least 1 wild-type allele (heterozygous); sufficient amount of functional enzyme
  • Ultra-fast metabolizer (UM)
    • Duplication of a wild-type allele; increased amount of functional enzyme

“In such cases, the mean dose indications widely used in the literature do not do justice to either fast or slow metabolizers.”5 Thus, depending on the CYP2D6 metabolization type, the dosage of nortryptiline must be varied between 10 mg and 500 mg.6
This explains why a significant number of ADHD sufferers (at least 1.5% to 7% in Europe) metabolize AMP and ATX much faster than usual and therefore suffer a significantly shortened duration of action of Attentin, Elvanse or Atomoxetine. 7 - 8% of those affected in Europe have reduced or absent CYP2D6 activity and therefore need to take much lower doses of AMP and ATX.

Enzyme variant Enzyme activity in vivo Enzyme activity in vitro
CYP2D6.1 normal normal
CYP2D6.3 inactive inactive
CYP2D6.4 inactive
CYP2D6.5 inactive
CYP2D6.6 inactive
CYP2D6.7 inactive
CYP2D6.9 decreased decreased
CYP2D6.10 decreased
CYP2D6.15 inactive
CYP2D6.16 inactive
Source: Kein, Grau (2001).2
Enzyme variant Activity Score (AS) Enzyme activity
*1/*1x2 3 UM
*1/*2x2 3 UM
*1x2/*10 2.25 NM
*1/*1 2 NM
*1/*2 2 NM
*2/*35 2 NM
*1/*17 1.5 NM
*1/*10x2 1.5 NM
*2/*29 1.5 NM
*35/*41 1.5 NM
*1/*10 1.25 NM
*10/*17x2 1.25 NM
*1/*4 1 IM
*2/*5 1 IM
*7/*35 1 IM
*9/*41 1 IM
*17/*41 1 IM
*10/17 0.75 IM
*10/*41 0.75 IM
*4/*9 0.5 IM
*5/*29 0.5 IM
*6/*17 0.5 IM
*4/*10 0.25 IM
*5/*10 0.25 IM
*4/*5 0 PM
*4x2/*6 0 PM
*5/*40 0 PMv
*1/*1062 N/A IM or NM
*4/*1273 N/A PM or IM
*106/*1274 N/A indeterminated
Source: Nofziger et al. (2020).7

The CYP2D6 gene is highly polymorphic. In Central Europe, particularly relevant are the alleles1

  • CYP2D6.3
  • CYP2D6.4
  • CYP2D6.5
  • CYP2D6.6
  • CYP2D6.9
  • CYP2D6.41

Poor metabolizers are likely to require lower AMP doses and ultrafast metabolizers are likely to require higher AMP doses. However, the effects of CYP2D6 polymorphisms on AMP metabolism are still unclear.8

One metastudy found that ultrarapid metabolizers (UM) may require up to 3 times the usual dose of medication; slow metabolizers (PM) may require as little as 20%. The variations are drug dependent and do not appear to be generalizable.9

In extensive CYP2D6 metabolizers, CYP2D6 inhibitors have been used to increase the response to atomoxetine.10

8.3.2.1. CYP2D6: substrates/inhibitors/inducers

The presentation is largely based on the compilation by Maucher (2019).11

*This list - like all information from ADxS.org - is not intended for your own therapeutic use. Even though we try to collect all information, the list is nevertheless incomplete. Errors can also not be excluded. Please ask your doctor or pharmacist. *

8.3.2.1.1. CYP2D6 substrates

Substrates metabolized by CYP2D6 include:121

  • Ajmaline
    • N-propylajmaline (an ajmaline derivative):6
      • 20 mg / day for long stem taboliiserene
      • 200 mg / day for ultrafast metabolizers
  • Alprenolol (beta blocker)
  • Amiflamine
  • Amitriptyline (Tricyclic AD)
  • Amoxapine
  • Amphetamine1310
    • AMP is degraded in several ways8
      • Hydroxylation by CYP2D6:12
        • 4-Hydroxyamphetamine
        • Norepinephrine (alphahydroxyamphetamine, norepephrine)
        • both are subject to further metabolism
        • One study found:14
          • Are CYP2D6 substrates and have been metabolized by CYP2D6
            • 4-methoxyamphetamine
            • 4-methoxy-nethylamphetamine
            • 4-methoxy-N-butylamphetamine
          • not against
            • Amphetamine
            • N-ethylamphetamine
            • N-butylamphetamine
    • oxidative deamination
    • CYP3A4 as the primary metabolization pathway to15
      • l-phenylpropan-2-one
        • is subsequently excreted as inactive benzoic acid
  • Aripiprazole (dopamine D2 partial agonist, neuroleptic)
  • Atomoxetine
    • Degradation mainly by CYP2D6 to 4-OH-atomoxetine (an active metabolite)
    • Low also by CYP2C19 to N-desmethylatomoxetine10
  • Betaxolol (beta blocker)
  • Brexpiprazole
  • Bufuralol (beta blocker)
  • Bupranolol (beta blocker)
  • Captopril
  • Cariprazine
  • Carvedilol (beta blocker)
  • Chloroquine
  • Chlorphenamine
  • Chlorpromazine
  • Chlorpropamide
  • Cinnarizine
  • Citalopram(weak)
  • Clomipramine (Tricyclic AD)
  • Clonidine
  • Clozapine (neuroleptic)
  • Codeine
    • No analgesic effect in long-chamber metabolizers because too little morphine is produced6
  • Debrisoquine
  • Delavirdin
  • Desipramine (Tricyclic AD)
  • Dexfenfluramine
  • Dexamphetamine / Dextroamphetamine / D-Amphetamine / D-Amfetamine
    • D-Amphetamine is metabolized by CYP2D6 according to some sources1617 , at least weakly18
    • According to other sources, d-amphetamine is metabolized without CYP involvement19
    • Another source describes CYP3A4 as the primary metabolic pathway15
  • Dexfenfluramine (Fenfluramine)
  • Dextromethorphan
  • Diphenhydramine
  • Dolasetron (HT3 receptor antagonist)
  • Donepezil
  • Doxepin (Tricyclic AD)
  • Doxorubicin
  • Duloxetine
  • Ecstasy / MDMA
  • Eliglustat
  • Elvanse (Lisdexamfetamine)
  • Encainide (antiarrhythmic drug)
  • Escitalopram(weak)
  • Flecainide (antiarrhythmic drug)
  • Fluoxetine (SSRI)
  • Flupentixol (neuroleptic)
  • Fluphenazine (neuroleptic)
  • Fluvoxamine
  • Galantamine
  • Guanoxone
  • Haloperidol (neuroleptic, dopamine antagonist)
  • HydrocodoneIbrutinib
  • Indoramine
  • Imipramine (Tricyclic AD)
  • Labetalol
  • Levomepromazine
  • Lidocaine
  • Lisdexamfetamine (sympathomimetic, amphetamine drug)
    • More precisely: Lisdexamfetamine is absorbed in the small intestine via the PEPT1 transporter (possibly also via PEPT2) and subsequently metabolized in the red blood cells to d-amphetamine and L-lysine. Lisdexamfetamine itself also does not inhibit or induce CYP2D6, CYP2C19, or CYP3A4.20 This metabolization to d-amphetamine does not occur via CYP2D6.
    • D-Amfetamine is metabolized by CYP2D6 according to some sources17 according to other sources without CYP involvement.19 at least weakly18
  • Lomustine
  • Maprotiline (tetracyclic antidepressant)
  • Methamphetamine
  • Methoxyamphetamine
  • Methoxyphenamine
  • Metoclopramide
  • Metoprolol (beta blocker)
  • Mexiletine (antiarrhythmic agent)
  • Mianserin (tetracycline antidepressant)
  • Minaprin
  • Mirtazapine
  • Moclobemide
  • Nebivolol
  • Nefazodon
  • Nicergoline
  • Nortriptyline (Tricyclic AD 2nd gen)
  • N-propylajmaline (antiarrhythmic agent)
  • Ondansetron (HT3 receptor antagonist)
  • Oxycodone
  • Palonosetron (HT3 receptor antagonist)
  • Paroxetine (SSRI)
  • Perazine (neuroleptic)
  • Perhexilin
  • Perphenazine (neuroleptic)
  • Phenacetin
  • Phenformin
  • Pindolol
  • Pimavanserin
  • Procainamide
  • Progesterone
  • Promethazine
  • Propafenone / propaphenone (antiarrhythmic agent)
  • Propranolol (beta blocker)
  • Protriptyline
  • Ramosetron (HT3 receptor antagonist)
  • Remoxipride (neuroleptic)
  • Risperidone (neuroleptic)
  • Rucaparib
  • Sertindol
  • Sertraline
  • Spartein (antiarrhythmic drug)
  • Tamoxifen
  • Tamsulosin
  • Thioridazine (neuroleptic)
  • Timolol (beta blocker)
  • Tolterodine
  • Tramadol (opioid)
  • Trifluperidol (neuroleptic)
  • Trimipramine (tricyclic antidepressant)
  • Tropisetron (HT3 receptor antagonist, serotonin antagonist)
  • Valbenazine
  • Venlafaxine (SNRI)
  • Viloxazine21 22
  • Zuclopenthixol (neuroleptic)
8.3.2.1.2. CYP2D6 inhibitors

Strong CYP2D6 inhibitors may cause:
up to more than 5-fold increase in plasma AUC levels
to over 80 percent decrease in clearance

  • Amiodarone
  • Bupropion (strong due to genetic downregulation)2324
  • Quinine, quinidine (strong) (tonic water, bitter lemon)
  • Celecoxib
  • Chlorphenamine
  • Chlorpromazine
  • Cinacalcet (strong)
  • Cimetidine
  • Citalopram (in vivo) (weak)
  • Clemastine
  • Clomipramine
  • Codeine
  • Cocaine
  • Desipramine (strong)
  • Diphenhydramine
  • Doxepin
  • Doxorubicin
  • Duloxetine (strong) (SSRI)24
  • Escitalopram (in vivo)(weak)
  • Efavirenz (HIV drug)25
  • Fluoxetine (strong) /SSRI)2412
  • Grapefruit
  • Ginseng (unclear)
  • Halofantrine
  • Haloperidol (strong)
  • Hydroxyzine
  • Imipramine (strong)
  • Kavapyrone
    • Isolated cases of liver damage in CYP2D6 deficiency6
  • Garlic
  • Cocaine (strong)
  • Levomepromazine
  • Methadone
  • Methylphenidate (weak)18
  • Metoclopramide
  • Mibefradil
  • Midodrine
  • Moclobemide
  • Norfluoxetine (active metabolite of fluoxetine)
  • Nortryptiline (in vitro)
  • Olanzapine
  • Panobinostat
  • Papaverine (in vitro)
  • Paroxetine (strong) (SSRI)2412
  • Pergolide (strong)
  • Perphenazine
  • Promethazine
  • Quetiapine
  • Ranitidine
  • Reboxetine
  • Risperidone
  • Ritonavir
  • Rolapitant
  • Ropinirole
  • Rucaparib
  • Selegiline
  • Sertraline (strong)12 ; doubtful26
  • Sidenafil (in vitro, presumably practically minor influence)
  • Divisionin
    • Was used to diagnose CYP2D6 metbolization type6
    • Toxic in CYP2D6 deficiency with multiple doses
  • Terbinafine
  • Ticlopidine
  • Trazodone (strong)
  • Tripelennamine
  • Valproate
  • Venlaflaxine (in vivo)
  • Yohimbine
  • Vitamin D / Colecalciferol
8.3.2.1.3. CYP2D6 inducers

CYP2D6 induction is rarely observed.

  • Dexamethasone (weak)
  • Efavirenz (HIV drug)25

  1. Phamarkogenetik.de: Cytochrom P450 2D6 (CYP2D6) [T88.7] Abruf 25.03.2022

  2. Kein, Grau (2001): Arzneimittelnebenwirkungen vermeiden: Möglichkeitender pharmakogenetischen Diagnostik. J Lab Med 2001; 25 (11/12): 477-484

  3. Kein, Grau (2001): Arzneimittelnebenwirkungen vermeidhen: Möglichkeitender pharmakogenetischen Diagnostik. J Lab Med 2001; 25 (11/12): 477-484

  4. Busse: Cytochrom P450 2D6 (CYP2D6), MVZ Martinsried GmbH, abgerufen 11.02,23

  5. Genetischer Polymorphismus: Biotransformationsenzyme; DAZ 1997, Nr. 40

  6. Hänsel R. (2010): Abnorme Phytopharmakawirkungen durch genetische Ursachen. In: Hänsel, Sticher (Herausgeber): Pharmakognosie – Phytopharmazie. 9. Aufl. S. 284 - 292

  7. Nofziger C, Turner AJ, Sangkuhl K, Whirl-Carrillo M, Agúndez JAG, Black JL, Dunnenberger HM, Ruano G, Kennedy MA, Phillips MS, Hachad H, Klein TE, Gaedigk A (2020): PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther. 2020 Jan;107(1):154-170. doi: 10.1002/cpt.1643. PMID: 31544239; PMCID: PMC6925641.

  8. Childress, Komolova, Sallee (2019): An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019 Nov;15(11):937-974. doi: 10.1080/17425255.2019.1675636. PMID: 31581854.

  9. Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I, Brockmöller J (2004): Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004 May;9(5):442-73. doi: 10.1038/sj.mp.4001494. PMID: 15037866.

  10. Schoretsanitis G, de Leon J, Eap CB, Kane JM, Paulzen M (2019): Clinically Significant Drug-Drug Interactions with Agents for Attention-Deficit/Hyperactivity Disorder. CNS Drugs. 2019 Dec;33(12):1201-1222. doi: 10.1007/s40263-019-00683-7. PMID: 31776871.

  11. Maucher (2019): CYP2D6. Gelbe Liste

  12. Konstantinidis: CYP-450-Interaktionen: Die Isoenzyme CYP1A2 und CYP2D6; Österreichische Gesellschaft für Neuropsychopharmakologie und Biologische Psychiatrie; Webseitenabruf 23.12.19

  13. Greiner (2010): Cytochrom-P450-Isoenzyme – Teil 2: Substrate, Induktoren und Inhibitoren- NeuroTransmitter 1.2010

  14. Bach MV, Coutts RT, Baker GB (1999): Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives. Xenobiotica. 1999 Jul;29(7):719-32. doi: 10.1080/004982599238344. PMID: 10456690.

  15. Stein MA, McGough JJ (2008): The pharmacogenomic era: promise for personalizing attention deficit hyperactivity disorder therapy. Child Adolesc Psychiatr Clin N Am. 2008 Apr;17(2):475-90, xi-xii. doi: 10.1016/j.chc.2007.11.009. PMID: 18295157; PMCID: PMC2413066.

  16. Ward K, Citrome L (2018): Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder. Expert Opin Drug Metab Toxicol. 2018 Feb;14(2):229-238. doi: 10.1080/17425255.2018.1420163. PMID: 29258368. REVIEW

  17. Gelbe Liste CYP2D6, Abruf 12.02.23

  18. Elbe, Black, McGrane, Procyshyn (2019): Clinical Handbook of Psychotropic Drugs für Children and Adolescents, 4. Auflage, S. 39

  19. Petri (2019): Analyse von CYP450-Wechselwirkungen: kleiner Aufwand, große Wirkung. Das Interaktionspotenzial der Stimulanzien und Nichtstimulanzien. Psychopharmakotherapie 2019;26:57–61.

  20. Pennick M (2010): Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat. 2010 Jun 24;6:317-27. doi: 10.2147/ndt.s9749. PMID: 20628632; PMCID: PMC2898170.

  21. Singh, Balasundaram, Singh (2022): Viloxazine for Attention-Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis of Randomized Clinical Trials. J Cent Nerv Syst Dis. 2022 May 20;14:11795735221092522. doi: 10.1177/11795735221092522. PMID: 35615643; PMCID: PMC9125110. REVIEW

  22. Edinoff, Akuly, Wagner, Boudreaux, Kaplan, Yusuf, Neuchat, Cornett, Boyer, Kaye, Kaye (2021): Viloxazine in the Treatment of Attention Deficit Hyperactivity Disorder. Front Psychiatry. 2021 Dec 17;12:789982. doi: 10.3389/fpsyt.2021.789982. PMID: 34975586; PMCID: PMC8718796., REVIEW

  23. Sager JE, Tripathy S, Price LS, Nath A, Chang J, Stephenson-Famy A, Isoherranen N (2017): In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation. Biochem Pharmacol. 2017 Jan 1;123:85-96. doi: 10.1016/j.bcp.2016.11.007. Erratum in: Biochem Pharmacol. 2021 Jan;183:114306. PMID: 27836670; PMCID: PMC5164944.

  24. Schoretsanitis, de Leon, Eap, Kane, Paulzen (2019): Clinically Significant Drug-Drug Interactions with Agents for Attention-Deficit/Hyperactivity Disorder. CNS Drugs. 2019 Dec;33(12):1201-1222. doi: 10.1007/s40263-019-00683-7.

  25. Gufford BT, Metzger IF, Bamfo NO, Benson EA, Masters AR, Lu JBL, Desta Z (2022): Influence of CYP2B6 Pharmacogenetics on Stereoselective Inhibition and Induction of Bupropion Metabolism by Efavirenz in Healthy Volunteers. J Pharmacol Exp Ther. 2022 Jul 7;382(3):313–26. doi: 10.1124/jpet.122.001277. PMID: 35798386; PMCID: PMC9426761.

  26. Hamelin, Turgeon, Vallée, Bélanger, Paquet, LeBel (1996): The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin. Clin Pharmacol Ther. 1996 Nov;60(5):512-21.

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