CYP2D6 Metabolizing enzyme
CYP2D6 influences drug degradation and dopamine synthesis.
CYP2D6 metabolizes around 25% of all active pharmaceutical ingredients12 , including the drugs relevant to the treatment of ADHD
- Vyvanse (AMP)
- Atomoxetine
- Nortryptiline
- Imipramine
- Desipramine (irrelevant today, strong inhibitor)
In addition, CYP2D6 is also involved in one of the dopamine synthesis pathways in humans by converting tyramine to dopamine.3 In rats, however, this is carried out by CYP2D2, CYP2D4 and CYP2D184
This alternative synthesis pathway appears to be quantitatively modest under normal physiological conditions in rats, but may be more efficient in the human brain and may be particularly important when the main synthesis pathway is impaired (e.g. tyrosine hydroxylase deficiency or aromatic amino acid decarboxylase deficiency). Furthermore, alternative CYP2D6-mediated dopamine synthesis could be relatively important in individuals who have more than one CYP2D6 gene (e.g. in Mediterranean populations).5
This raises the question of whether people with particularly active CYP2D6 gene variants could have increased dopamine synthesis and increased dopamine degradation as a result and whether people with particularly low CYP2D6 gene variants could have reduced dopamine synthesis and reduced dopamine degradation as a result. We are not yet aware of any studies on this.
- 1. CYP2D6 gene variants influence the rate of metabolism
- 2. POR gene variants influence CYP2D6 metabolism rate
- 3. HNF4α gene variants influence CYP2D6 metabolism rate
- 4. CYP2D6: substrates/inhibitors/inducers
1. CYP2D6 gene variants influence the rate of metabolism
A CYP2D6 gene defect is inherited in an autosomal recessive manner.
Based on the experience with the influence of CYP2D6 on the effect of other drugs, the different CYP2D6 gene variants lead to different types of metabolization2
- Approx. 90 %6 of Europeans carry the wild type or a heterozygous defect
- Approx. 7%2 to just under 10%6 of Europeans carry a homozygous enzyme defect
- CYP2D6 has limited performance
- Carriers are “poor metabolizers (PM)”
- Effects amplified
- Increased risk of side effects
- Particularly slow dosing is important
- Particularly low dosage helpful
- In contrast, around 1.5%7 to 7%2 of Europeans have up to 12 active CYP2D6 copies
- CYP2D6 is hyper-powerful
- Carriers are “ultra-fast metabolizers”
- Accelerated degradation of drugs
- Can lead to ineffectiveness
- Especially for drugs with a high first-pass effect
- Is associated with therapy resistance (non-responders)
- Increased dose / more frequent dosing can be helpful
- Accelerated degradation of drugs
A more general distinction between the types of metabolization is as follows:68
- Slow metabolizer (PM)
- No wild-type allele present (homozygous mutant); both alleles inactive, no sufficient 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 average doses reported in the literature do not do justice to either fast or slow metabolizers.”9 Depending on the CYP2D6 metabolization type, the dosage of nortryptiline must be varied between 10 mg and 500 mg.10
The duration of action of a single dose of atomoxetine varied from 5.2 hours in fast metabolizers to 21.6 hours in slow metabolizers.11 Several other studies have looked at the variation in the effect of atomoxetine in relation to different CYP2D6 metabolization types.12121314151515
The large fluctuations in the duration of action of some ADHD drugs degraded by CYP2D6 (in 2/3 of people with ADHD, a single dose of Vyvanse only works for 7 hours or even less) cannot be explained by CYP2D6 gene variants alone.
The effectiveness of CYP2D6 degradation is influenced by gene variants of the POR gene (cytochrome P450 oxidoreductase)1
The excretion of AMP depends strongly on the pH value of the urinary tract and the flow rates. The excretion of AMP in the urine is between 1 % and 75 %, the rest is metabolized via the liver. At normal urinary pH levels, 30% to 40% of the dose is excreted as unchanged parent compound and approximately 50% of the dose is excreted as alpha-hydroxyamphetamine or its downstream inactive metabolite, hippuric acid. Since AMP is a weak base with a pKa value of 9.9, it is excreted quickly; if the urine is acidic (pH <6,0). Ist der Urin alkalisch (pH >7.5), excretion is delayed. Accordingly, the relative amounts of AMP and the excreted metabolites differ depending on the pH conditions in the urine. The t1/2 of AMP should increase by about 7 hours for each unit of increase in urine pH. Large deviations from normal physiological values may occur, especially when taking acidifying or alkalizing agents16
Comedication with CYP2D6 substrates, inhibitors or inducers also influences the AMP duration of action.
Berberine, quinine, bupropion as Vyvanse duration of action extenders
Berberine is a very long-lasting, “quasi-irreversible” inhibitor of CYP2D6.
We have received several individual case reports from people with ADHD who were able to prolong the effect of a single dose of Vyvanse, which was clearly too short, by taking Berberine as an augmentation.
- One person with ADHD reported that 300 mg was sufficient for this, but 150 mg was not. He thus achieved a duration of action of around 8 to 10 hours from a single dose of Vyvanse instead of the previous 4 to 6 hours, and also felt that the effect was more constant.
- Another reported that he was able to reduce his previous three-dose Vyvanse intake of 50/20/20 (which was accompanied by crashes and drug fluctuations) to 40/0/0 with 1000 mg berberine, which worked consistently and evenly throughout the day. A later further (second) Vyvanse dose led to sleep problems with berberine, presumably due to the now much longer effect.
- A third person with ADHD reported an optimal dose for him of 500 mg berberine in order to adequately prolong the duration of action of Vyvanse, which had previously been too short for him.
There are also indications of a corresponding effect of quinine (tonic, bitter lemon) or bupropion.
One person with ADHD reported a significantly stronger and longer effect of Vyvanse from augmented bupropion than from augmented berberine or quinine.
7 - 8 % of people with ADHD in Europe have reduced or absent CYP2D6 activity and therefore need to take much lower doses of AMP, ATX or other drugs metabolized by CYP2D6, in the case of AMP even at normal urine pH levels.
| 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 | reduced | |
| CYP2D6.15 | inactive | |
| CYP2D6.16 | inactive | |
| Source: Kein, Grau (2001).6 |
| 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 | indeterminate |
| Source: Nofziger et al. (2020).17 |
A much more comprehensive description of the different CYP2D6 variants can be found at Pharmavar.org (formerly www.cypalleles.ki.se).
The CYP2D6 gene is highly polymorphic. In Central Europe, the following alleles are particularly relevant2
- CYP2D6.3
- CYP2D6.4
- CYP2D6.5
- CYP2D6.6
- CYP2D6.9
- CYP2D6.41
Poor metabolizers may require lower doses of AMP and ultra-rapid metabolizers may require higher doses of AMP. A meta-analysis found that ultra-rapid metabolizers (UM) may require up to 3 times the usual dose of medication, while slow metabolizers (PM) may require up to 20%. The deviations are drug-dependent and do not appear to be generalizable.18 However, the effects of CYP2D6 polymorphisms on AMP metabolism are still unclear.16
In extensive CYP2D6 metabolizers, CYP2D6 inhibitors were used to increase the response to atomoxetine.19
CYP2D6 is also involved in dopamine synthesis via the alternative dopamine synthesis pathway via P-tyrosine and in serotonin synthesis via 5-methoxytryptamine.203
Unexpectedly high hepatic exposure to atomoxetine has been reported in patients with intermediate metabolism who have CYP2D610 or 2D636 alleles.21
2. POR gene variants influence CYP2D6 metabolism rate
The effectiveness of CYP2D6 degradation is influenced by gene variants of the POR gene (cytochrome P450 oxidoreductase, NADPH P450 oxidoreductase, CPR) in addition to the CYP2D6 gene variants.122 The enzyme encoded by POR is required for electron transfer from NADP to cytochrome P450 in microsomes and provides electron transfer to heme oxygenase and cytochrome B5.23 Each POR gene variant affects each CYP differently. The effect on CYP2D6 can therefore not be transferred to other CYPs.
POR (CPR) decreases with age and was 27% lower in men over 45 than in men under 45. As CYP levels also decreased, the ratio remains approximately the same.24
The different gene variants have different influences on CYP2D6 metabolization:1
- Q153R
- rare variant
- increased CYP2D6 activity in
- Bufuralol: 153 %
- EOMCC: 128 %
- Dextromethorphan: 198 %
- A287P
- no detectable CYP2D6 activity
- EOMCC (2H-1-benzopyran-3-carbonitrile,7-(ethoxy-methoxy)-2-oxo-(9Cl)): 0 %
- reduced CYP2D6 activity in
- Bufuralol: 25 %
- Dextromethorphan: 25%
- no detectable CYP2D6 activity
- R457H
- no detectable CYP2D6 activity
- EOMCC: 0 %
- no detectable CYP2D6 activity
- A503V
There are no studies to date on the effect on ADHD drugs metabolized by CYP2D6. Estimates can therefore only be made on the basis of the effect on other drugs metabolized by CYP2D6.
Other studies, in particular by the research group of Flück et al, investigated the effect of different gene variants on CYP3A426 CYP17A127 and CYP19A128
As the work by Flück et al. shows, the influences of the POR gene variants on the activity of various CYP 450 enzymes are not identical, but roughly comparable. Only Q153R differs massively in relation to CYP17A1. From this it is possible to deduce approximately what influence the POR gene variants could have on CYP 450 enzymes that have not been investigated.
| Gene variant | in % of the wild type of CYP2D6 | in % of the wild type of CYP3A4 | in % of the wild type of CYP17A1 | in % of the wild type of CYP19A1 |
|---|---|---|---|---|
| Wild type | 100 % | 100 % | 100 % | 100 % |
| A115V | 85 % | 63 % | ||
| T142A | 85 % | 49 % | ||
| Q153R | 128 % to 198 % | 119 % | 9 % | 189 % |
| Y181D | 0 % | 0 % | 0 % | |
| P228L | 101 % | 75 % | 60 % | |
| M263V | 76 % | |||
| A287P | 0 % to 25 % | 26 % | 9 % | |
| R316W | 110 % | 61 % | 97 % | |
| G413S | 100 % | 76 % | 105 % | |
| R457H | 0 % | 0 % | 0.7 % | |
| Y459H | 0 % | 0.4 % | ||
| V492E | 0 % | 0.3 % | ||
| A503V | 53 % to 85 % | 107 % | 69 % | |
| G504R | 93 % | 53 % | 72 % | |
| G539R | 9 % | 12 % | ||
| L565P | 14 % | |||
| C569Y | 32 % | 6 % | ||
| Y607C | 9 % | |||
| V608F | 16 % | 8 % | ||
| R616X | 0 % | 0 % | 0 % | |
| V631I | 89 % | 74 % | 47 % | |
| F646del | 88 % | 36 % | 23 % |
The POR gene variant can be determined by a laboratory test.
3. HNF4α gene variants influence CYP2D6 metabolism rate
HNF4α gene variants regulate the activity of CYP2D6.2930
4. CYP2D6: substrates/inhibitors/inducers
The presentation is largely based on the compilation by Maucher (2019).31
This list - like all information from ADxS.org - is not intended for personal therapeutic use. Even though we endeavor to collect all information, the list is nevertheless incomplete. Errors cannot be ruled out. Please ask your doctor or pharmacist.
4.1. CYP2D6 substrates
Substrates that are metabolized by CYP2D6 include322
- 5-Methoxytryptamine
- CYP2D6 is a step in serotonin synthesis via the alternative dopamine synthesis pathway via 5-methoxytryptamine20
- Ajmaline
- N-propylajmaline (an ajmaline derivative):10
- 20 mg / day for slow-release tablets
- 200 mg / day for ultrafast metabolizers
- N-propylajmaline (an ajmaline derivative):10
- Alprenolol (beta blocker)
- Amiflamine
- Amitriptyline (tricyclic AD)33
- Amoxapine
- Amphetamine341933
- AMP is broken down in various ways:
- Hydroxylation by CYP2D6:3235
- 4-Hydroxyamphetamine
- Noradrenaline (alpha-hydroxyamphetamine, norepinephrine)
- both are subject to a further metabolism
- One study found:36
- Are CYP2D6 substrates and have been metabolized by CYP2D6
- 4-methoxyamphetamine
- 4-methoxy-nethylamphetamine
- 4-methoxy-N-butylamphetamine
- not against it
- Amphetamine
- N-ethylamphetamine
- N-butylamphetami
- Are CYP2D6 substrates and have been metabolized by CYP2D6
- One study found little evidence of metabolization of amphetamine drugs by CYP2D637
- Hydroxylation by CYP2D6:3235
- oxidative deamination
- CYP3A4 metabolized to38
- l-phenylpropan-2-one
- is then excreted as inactive benzoic acid
- l-phenylpropan-2-one
- AMP is broken down in various ways:
- Aprinidine33
- Aripiprazole (dopamine D2 partial agonist, neuroleptic)33
- Atomoxetine33
- Degradation mainly by CYP2D6 to 4-OH-atomoxetine (an active metabolite)
- Low also by CYP2C19 to N-desmethylatomoxetine19
- Betaxolol (beta blocker)
- Brexpiprazole
- Bufuralol (beta blocker)33
- Bupranolol (beta blocker)
- Captopril
- Cariprazine
- Carvedilol (beta blocker)33
- Chloroquine
- Chlorphenamine
- Chlorpromazine33
- Chlorpropamide
- Cinnarizine
- Citalopram(weak)
- Clomiphene33
- Clomipramine (tricyclic AD)
- Clonidine
- Clozapine (neuroleptic)
- Codeine33
- No analgesic effect in slow metabolizers because too little morphine is produced10
- Debrisoquine33
- Delavirdin
- Desipramine (tricyclic AD)33
- Dexfenfluramine
- Dexamphetamine / Dextroamphetamine / D-Amphetamine / D-Amfetamine
- Dexfenfluramine (Fenfluramine)
- Dextromethorphan33
- Dihydrocodeine33
- Diphenhydramine33
- Dolasetron (HT3 receptor antagonist)33
- Donepezil33
- Doxepin (tricyclic AD)
- Doxorubicin
- Duloxetine33
- Ecstasy (MDMA, N-methyl-3,4-methylenedioxyamphetamine)33
- Eliglustat
- Vyvanse (lisdexamfetamine)
- Encainide (antiarrhythmic drug)
- Escitalopram(weak)
- Flecainide (antiarrhythmic drug)33
- Fluoxetine (SSRI)
- Flupentixol (neuroleptic)
- Fluphenazine (neuroleptic)
- Fluvoxamine44
- Galantamine33
- Guanoxone
- Haloperidol (neuroleptic, dopamine antagonist)
- Hydrocodone33
- Ibrutinib
- Indoramin
- Imipramine (tricyclic AD) 33
- Labetalol
- Levomepromazine
- Lidocaine
- Lisdexamfetamine (amphetamine prodrum)
- Lisdexamfetamine is absorbed in the small intestine via the PEPT1 transporter (possibly also via PEPT2) and then metabolized in the red blood cells to d-amphetamine and L-lysine. Lisdexamfetamine itself does not inhibit or induce CYP2D6, CYP2C19 or CYP3A4.45 This metabolization to d-amphetamine does not occur via CYP2D6.
- Lisdexamfetamine thus becomes D-amphetamine (dextroamphetamine). This is probably metabolized by CYP2D6. See above under amphetamine
- Lomustine
- Loratadine33
- Maprotiline (tetracyclic antidepressant)
- MDMA (N-methyl-3,4-methylenedioxyamphetamine, ecstasy)33
- Methamphetamine
- Methoxyamphetamine
- Methoxyphenamine
- Metoclopramide4633
- Metoprolol (beta blocker)33
- Mexiletine (antiarrhythmic drug)33
- Mianserin (tetracyclic antidepressant)33
- Minaprin33
- Mirtazapine33
- Moclobemide
- N-methyl-3,4-methylenedioxyamphetamine (MDMA, ecstasy)33
- Nebivolol
- Nefazodon
- Nicergoline
- Nortriptyline (tricyclic AD 2nd gen.)33
- N-propylajmaline (antiarrhythmic drug)
- Ondansetron (HT3 receptor antagonist)33
- Oxycodone33
- Palonosetron (HT3 receptor antagonist)
- Paroxetine (SSRI)33
- Perazine (neuroleptic)
- Perhexiline33
- Perphenazine (neuroleptic)
- Phenacetin
- Phenformin
- Pindolol
- Pimavanserin
- Procainamide33
- Progesterone
- Promethazine33
- Propafenone / propaphenone (antiarrhythmic drug)33
- Propranolol (beta blocker)33
- Protriptyline
- Ramosetron (HT3 receptor antagonist)
- Remoxipride (neuroleptic)
- Risperidone (neuroleptic)33
- Rucaparib
- Salbutamol44
- Sertindol
- Sertraline
- Spartein (antiarrhythmic drug)33
- Tamoxifen33
- Tamsulosin
- Thioridazine (neuroleptic)33
- Timolol (beta blocker)33
- Tolterodine
- Tramadol (opioid)33
- Trifluperidol (neuroleptic)
- Trimipramine (tricyclic antidepressant)
- Tropisetron (HT3 receptor antagonist, serotonin antagonist)33
- P-Tyrosine
- Valbenazine
- Venlafaxine (SNRI)33
- Viloxazine47 48
- Zuclopenthixol (neuroleptic)33
4.2. CYP2D6 inhibitors
Strong CYP2D6 inhibitors can cause:
up to over 5-fold increase in plasma AUC values
up to over 80 percent decrease in clearance
- Amiodarone
- Berberine (very strong and quasi-irreversible = very long-lasting)(KI: 4.29 µM; kinact: 0.025 min-1)4950
- Bupropion (strong due to genetic downregulation)515233
- Quinine (strong) (tonic water, bitter lemon)
- Quinidine = Quinidine33
- Celecoxib33
- Chlorphenamine
- Chlorpromazine
- Cinacalcet (strong)
- Cimetidine
- Citalopram (in vivo) (weak)
- Clemastine
- Clomipramine
- Codeine
- Cocaine (strong) = cocaine
- Desipramine (strong)
- Diltiazem (quasi-irreversible)49
- Diphenhydramine
- Doxepin
- Doxorubicin
- Duloxetine (strong) (SSRI)52
- Escitalopram (in vivo)(weak)
- Efavirenz (HIV medication)53
- Flecainide33
- Fluoxetine (strong) /SSRI)523233
- Inhibiting in the nucleus accumbens and striatum, inducing in the cerebellum20
- Grapefruit
- Ginseng (unclear)
- Halofantrine
- Haloperidol (strong)33
- Hydroxyzine
- Imipramine (strong)
- Cavapyrone
- Individual cases of liver damage with CYP2D6 deficiency10
- Garlic
- Cocaine (strong) = Cocaine
- Levomepromazine
- Methadone33
- Methylphenidate (weak)41
- Metoclopramide46
- Mibefradil
- Midodrine
- Mifepristone (irreversible inhibitor)49
- Moclobemide
- Norfluoxetine (active metabolite of fluoxetine)
- Nortryptiline (in vitro)
- Olanzapine
- Panobinostat
- Papaverine (in vitro)
- Paroxetine (strong) (SSRI)523233
- Pergolide (strong)
- Perphenazine
- Promethazine
- Quetiapine
- Quinidine = quinidine33
- Ranitidine
- Reboxetine
- Risperidone
- Ritonavir
- Rolapitant
- Ropinirole
- Rucaparib
- Selegiline
- Sertraline (strong)32 ; doubtful54
- Sidenafil (in vitro, presumably practically negligible influence)
- Division
- Was used to diagnose the CYP2D6 metabolization type10
- Toxic in case of CYP2D6 deficiency with multiple doses
- Terbinafine
- Thioridazine
- Inhibiting in nucleus accumbens and substantia nigra, inducing in striatum and cerebellum20
- Ticlopidine
- Trazodone (strong)
- Triple amine
- Valproate
- Venlaflaxine (in vivo)
- Yohimbine
- Vitamin D / Colecalciferol
4.3. CYP2D6 inducers
CYP2D6 induction is rarely observed.
- Clozapine
- Inducing in the cerebellum, brain stem, olfactory bulb, other brain regions, inhibiting in the nucleus accumbens, substantia nigra20
- Dexamethasone (weak)
- Efavirenz (HIV medication)53
- Fluoxetine (SSRI)
- Inducing in cerebellum, inhibiting in nucleus accumbens and striatum20
- Nefazodon
- Inducing in the brain stem20
- Nicotine55
- The increased rate of smokers with ADHD could be due not only to the receptor effects of nicotine, but also to increased dopamine synthesis (via the alternative dopamine synthesis pathway via P-tyrosine) and the detoxification of neurotoxins via CYP2D6 induction by nicotine20
- Rifampin56
- Thioridazine
- Inducing in the striatum and cerebellum, inhibiting in the nucleus accumbens and substantia nigra20
Sandee D, Morrissey K, Agrawal V, Tam HK, Kramer MA, Tracy TS, Giacomini KM, Miller WL (2010): Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro. Pharmacogenet Genomics. 2010 Nov;20(11):677-86. doi: 10.1097/FPC.0b013e32833f4f9b. PMID: 20940534; PMCID: PMC5708132. ↥ ↥ ↥ ↥
Phamarkogenetik.de: Cytochrom P450 2D6 (CYP2D6) [T88.7] Abruf 25.03.2022 ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥
Niwa T, Shizuku M, Yamano K (2017): Effect of genetic polymorphism on the inhibition of dopamine formation from p-tyramine catalyzed by brain cytochrome P450 2D6. Arch Biochem Biophys. 2017 Apr 15;620:23-27. doi: 10.1016/j.abb.2017.03.009. PMID: 28347660. ↥ ↥ ↥
Anna Haduch A, Bromek E, Daniel WA (2013): Role of brain cytochrome P450 (CYP2D) in the metabolism of monoaminergic neurotransmitters. Pharmacol Rep. 2013;65(6):1519-28. doi: 10.1016/s1734-1140(13)71513-5. PMID: 24553000. ↥
Haduch A, Bromek E, Daniel WA (2013): Role of brain cytochrome P450 (CYP2D) in the metabolism of monoaminergic neurotransmitters. Pharmacol Rep. 2013;65(6):1519-28. doi: 10.1016/s1734-1140(13)71513-5. PMID: 24553000. ↥
Kein, Grau (2001): Arzneimittelnebenwirkungen vermeiden: Möglichkeitender pharmakogenetischen Diagnostik. J Lab Med 2001; 25 (11/12): 477-484 ↥ ↥ ↥ ↥
Kein, Grau (2001): Arzneimittelnebenwirkungen vermeidhen: Möglichkeitender pharmakogenetischen Diagnostik. J Lab Med 2001; 25 (11/12): 477-484 ↥
Busse: Cytochrom P450 2D6 (CYP2D6), MVZ Martinsried GmbH, abgerufen 11.02,23 ↥
Genetischer Polymorphismus: Biotransformationsenzyme; DAZ 1997, Nr. 40 ↥
Hänsel R. (2010): Abnorme Phytopharmakawirkungen durch genetische Ursachen. In: Hänsel, Sticher (Herausgeber): Pharmakognosie – Phytopharmazie. 9. Aufl. S. 284 - 292 ↥ ↥ ↥ ↥ ↥
Trzepacz PT, Williams DW, Feldman PD, Wrishko RE, Witcher JW, Buitelaar JK (2008): CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD. Eur Neuropsychopharmacol. 2008 Feb;18(2):79-86. doi: 10.1016/j.euroneuro.2007.06.002. PMID: 17698328. ↥
Michelson D, Read HA, Ruff DD, Witcher J, Zhang S, McCracken J (2007): CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry. 2007 Feb;46(2):242-51. doi: 10.1097/01.chi.0000246056.83791.b6. PMID: 17242628. ↥ ↥
Brown JT, Bishop JR, Sangkuhl K, Nurmi EL, Mueller DJ, Dinh JC, Gaedigk A, Klein TE, Caudle KE, McCracken JT, de Leon J, Leeder JS (2019): Clinical Pharmacogenetics Implementation Consortium Guideline for Cytochrome P450 (CYP)2D6 Genotype and Atomoxetine Therapy. Clin Pharmacol Ther. 2019 Jul;106(1):94-102. doi: 10.1002/cpt.1409. PMID: 30801677; PMCID: PMC6612570. ↥
Brown JT, Abdel-Rahman SM, van Haandel L, Gaedigk A, Lin YS, Leeder JS (2016): Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD. Clin Pharmacol Ther. 2016 Jun;99(6):642-50. doi: 10.1002/cpt.319. PMID: 26660002; PMCID: PMC4862932. ↥
Yu G, Li GF, Markowitz JS (2016): Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition. J Child Adolesc Psychopharmacol. 2016 May;26(4):314-26. doi: 10.1089/cap.2015.0137. PMID: 26859445; PMCID: PMC4876529. REVIEW ↥ ↥ ↥
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. ↥ ↥
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. ↥
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. ↥
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. ↥ ↥ ↥
Haduch A, Bromek E, Daniel WA (2013): Role of brain cytochrome P450 (CYP2D) in the metabolism of monoaminergic neurotransmitters. Pharmacol Rep. 2013;65(6):1519-28. doi: 10.1016/s1734-1140(13)71513-5. PMID: 24553000. REVIEW ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥
Shimizu M, Uehara S, Ohyama K, Nishimura H, Tanaka Y, Saito Y, Suemizu H, Yoshida S, Yamazaki H (2023): Pharmacokinetic Models Scaled-up from Humanized-liver Mouse Data Can Account for Drug Monitoring Results of Atomoxetine and Its 4-Hydroxylated and N-Demethylated Metabolitesin Pediatric Patients Genotyped for Cytochrome P450 2D6. Drug Metab Dispos. 2023 Oct 25:DMD-AR-2023-001481. doi: 10.1124/dmd.123.001481. PMID: 37879849. ↥
Ding S, Yao D, Deeni YY, Burchell B, Wolf CR, Friedberg T (2001): Human NADPH-P450 oxidoreductase modulates the level of cytochrome P450 CYP2D6 holoprotein via haem oxygenase-dependent and -independent pathways. Biochem J. 2001 Jun 1;356(Pt 2):613-9. doi: 10.1042/0264-6021:3560613. PMID: 11368792; PMCID: PMC1221876. ↥
Gan L, von Moltke LL, Trepanier LA, Harmatz JS, Greenblatt DJ, Court MH (2009): Role of NADPH-cytochrome P450 reductase and cytochrome-b5/NADH-b5 reductase in variability of CYP3A activity in human liver microsomes. Drug Metab Dispos. 2009 Jan;37(1):90-6. doi: 10.1124/dmd.108.023424. PMID: 18838505; PMCID: PMC2610240. ↥
Miller WL, Huang N, Agrawal V, Giacomini KM (2009): Genetic variation in human P450 oxidoreductase. Mol Cell Endocrinol. 2009 Mar 5;300(1-2):180-4. doi: 10.1016/j.mce.2008.09.017. PMID: 18930113. REVIEW ↥ ↥
Flück CE, Mullis PE, Pandey AV (2010): Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism. Biochem Biophys Res Commun. 2010 Oct 8;401(1):149-53. doi: 10.1016/j.bbrc.2010.09.035. PMID: 20849814. ↥
Flück CE, Nicolo C, Pandey AV (2007): Clinical, structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductase. Fundam Clin Pharmacol. 2007 Aug;21(4):399-410. doi: 10.1111/j.1472-8206.2007.00520.x. PMID: 17635179. REVIEW ↥
Flück CE, Pandey AV (2017): Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt A):64-70. doi: 10.1016/j.jsbmb.2016.03.031. PMID: 27032764. ↥
Lee SS, Cha EY, Jung HJ, Shon JH, Kim EY, Yeo CW, Shin JG (2008): Genetic polymorphism of hepatocyte nuclear factor-4alpha influences human cytochrome P450 2D6 activity. Hepatology. 2008 Aug;48(2):635-45. doi: 10.1002/hep.22396. PMID: 18666237. ↥
Hara H, Adachi T (2002):Contribution of hepatocyte nuclear factor-4 to down-regulation of CYP2D6 gene expression by nitric oxide. Mol Pharmacol. 2002 Jan;61(1):194-200. doi: 10.1124/mol.61.1.194. PMID: 11752221. ↥
Konstantinidis: CYP-450-Interaktionen: Die Isoenzyme CYP1A2 und CYP2D6; Österreichische Gesellschaft für Neuropsychopharmakologie und Biologische Psychiatrie; Webseitenabruf 23.12.19 ↥ ↥ ↥ ↥ ↥
Zanger UM, Schwab M (2012): Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013 Apr;138(1):103-41. doi: 10.1016/j.pharmthera.2012.12.007. PMID: 23333322. REVIEW ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥
Greiner (2010): Cytochrom-P450-Isoenzyme – Teil 2: Substrate, Induktoren und Inhibitoren- NeuroTransmitter 1.2010 ↥
Childress AC, Komolova M, Sallee FR (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. Epub 2019 Nov 8. PMID: 31581854. REVIEW ↥
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. ↥
Law R, Lewis D, Hain D, Daut R, DelBello MP, Frazier JA, Newcorn JH, Nurmi E, Cogan ES, Wagner S, Johnson H, Lanchbury J (2022):. Characterisation of seven medications approved for attention-deficit/hyperactivity disorder using in vitro models of hepatic metabolism. Xenobiotica. 2022 Jul;52(7):676-686. doi: 10.1080/00498254.2022.2141151. PMID: 36317558. ↥
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. ↥
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 ↥
Gelbe Liste CYP2D6, Abruf 12.02.23 ↥
Elbe, Black, McGrane, Procyshyn (2019): Clinical Handbook of Psychotropic Drugs für Children and Adolescents, 4. Auflage, S. 39 ↥ ↥
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. ↥
Petri (2019): Analyse von CYP450-Wechselwirkungen: kleiner Aufwand, große Wirkung. Das Interaktionspotenzial der Stimulanzien und Nichtstimulanzien. Psychopharmakotherapie 2019;26:57–61. ↥
Marques L, Vale N (2023): Prediction of CYP-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Modeling: A Case Study of Salbutamol and Fluvoxamine. Pharmaceutics. 2023; 15(6):1586. https://doi.org/10.3390/pharmaceutics15061586 ↥ ↥
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. ↥
Desta Z, Wu GM, Morocho AM, Flockhart DA (2002): The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6. Drug Metab Dispos. 2002 Mar;30(3):336-43. doi: 10.1124/dmd.30.3.336. PMID: 11854155. ↥ ↥
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 ↥
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 ↥
Kim HG, Lee HS, Jeon JS, Choi YJ, Choi YJ, Yoo SY, Kim EY, Lee K, Park I, Na M, Park HJ, Cho SW, Kim JH, Lee JY, Kim SK (2020): Quasi-Irreversible Inhibition of CYP2D6 by Berberine. Pharmaceutics. 2020 Sep 24;12(10):916. doi: 10.3390/pharmaceutics12100916. PMID: 32987920; PMCID: PMC7600264. ↥ ↥ ↥
Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH (2012): Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol. 2012 Feb;68(2):213-7. doi: 10.1007/s00228-011-1108-2. PMID: 21870106; PMCID: PMC4898966. ↥
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. ↥
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. ↥ ↥ ↥ ↥
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. ↥ ↥
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. ↥
Miksys S, Tyndale RF (2006): Nicotine induces brain CYP enzymes: relevance to Parkinson’s disease. J Neural Transm Suppl. 2006;(70):177-80. doi: 10.1007/978-3-211-45295-0_28. PMID: 17017527. ↥
Caraco Y, Sheller J, Wood AJ (1997): Pharmacogenetic determinants of codeine induction by rifampin: the impact on codeine’s respiratory, psychomotor and miotic effects. J Pharmacol Exp Ther. 1997 Apr;281(1):330-6. PMID: 9103514. ↥