CYP3A4 Metabolizing enzyme

• 8.3.1. CYP3A4
  • 8.3.1.1. CYP3A4 gene variants influence the rate of metabolism
  • 8.3.1.2. POR gene variants influence CYP3A4 metabolism rate
  • 8.3.1.3. CYP3A4 substrates / CYP3A4 inhibitors / CYP3A4 inducers
    • 8.3.1.3.1. CYP3A4 substrates
    • 8.3.1.3.2. CYP3A4 inhibitors
    • 8.3.1.3.2.1. CYP3A4 inhibitors and guanfacine
    • 8.3.1.3.3. CYP3A4 inducers
    • 8.3.1.3.3.1. CYP3A4 inducers and guanfacine
    • 8.3.1.3.4. Other interactions of guanfacine

8.3.1. CYP3A4¶

CYP3A4 accounts for the largest proportion of cytochromes at 29 % (liver). CYP3A4 metabolizes a good 30 %¹ (according to other sources 40 to 50 %) of the drugs in common use and is therefore the most important CYP 450 enzyme.
Relevant ADHD drugs are metabolized via CYP3A4:

• Guanfacine

CYP3A4 is expressed in the gastrointestinal tract and the liver and is particularly involved in the metabolization of large lipophilic molecules (e.g. endogenous steroids). The most potent inhibitors of the isoenzyme include the azole antifungal drug ketoconazole and the protease inhibitor ritonavir.

CYP3A4 is more active in women than in men,² so women may require higher doses of drugs metabolized via CYP3A4 than men.
There are also interactions that increase (inducers) or inhibit (inhibitors) the enzyme activity of CYP3A4.

In vitro, the 3-OH guanfacine signaling pathway accounted for at least 2.6% of guanfacine metabolism in cryopreserved, plated human hepatocytes and 71% in pooled human liver microsomes.³

8.3.1.1. CYP3A4 gene variants influence the rate of metabolism¶

The influence of gene variants on metabolization by CYP3A4 appears to be weaker than for other CYP 450 enzymes.

The following CYP3A4 gene variants have been reported to have an effect on metabolism:⁴

• I118V: reduced activity
• R130Q: no protein formation
• T185S on allele 16A: reduced protein formation and activity
• T185S on allele 16B: reduced activity
• F189S: reduced activity
• P218R: reduced activity
• S222P: reduced activity
• R268* Reduced activity; no protein formation
• 277-Frameshift: reduced activity
• L293P: low midazolam clearance / increased tacrolism clearance / unchanged activity / increased activity
• T363M: reduced protein formation and activity
• L373F: reduced protein formation and activity
• P416L: no protein formation
• 488-frameshift: low midazolam clearance / no protein formation
• intron 6 C15389T reduced activity

8.3.1.2. POR gene variants influence CYP3A4 metabolism rate¶

The effectiveness of CYP3A4 degradation is influenced by gene variants of the POR gene (cytochrome P450 oxidoreductase, NADPH P450 oxidoreductase, CPR) in addition to the CYP3A4 gene variants.⁵ 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 B5.⁶ 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.⁷

There are no studies to date on the effect on ADHD drugs metabolized by CYP3A4. Estimates can therefore only be made on the basis of the effect on other drugs metabolized by CYP3A4.

Studies, in particular by the research group of Flück et al, investigated the effect of different gene variants on the metabolization of CYP2D6⁸, CYP3A4⁵, CYP17A1⁹ and CYP19A1¹⁰.
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 %

In contrast, one study found only a minor influence of POR on the efficacy of CYP3A4 degradation (here: of midazolam).⁷

The POR gene variant can be determined by a laboratory test.

8.3.1.3. CYP3A4 substrates / CYP3A4 inhibitors / CYP3A4 inducers¶

The presentation is based on the compilation by Maucher (2019)¹¹ and has been expanded and supplemented by us.

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.

8.3.1.3.1. CYP3A4 substrates¶

Substrate: binds to (here: is metabolized by) CYP3A4.

• Abemaciclib
• Acalabrutinib
• Albuterol
• Alectinib
• Alfentanil
• Alprazolam
• Amiodarone
• Amitriptyline
• Amlodipine
• Amprenavir
• Aprepitant
• Aripiprazole
• Artemether
• Astemizole
• Atazanavir
• Atorvastatin
• Boceprevir
• Brexpiprazole
• Brigatinib
• Buspirone
• Carbamazepine
• Cariprazine
• Cerivastatin
• Quinidine
• Quinine (tonic water, bitter lemon)
• Chlorphenamine
• Ciclosporin
• Cilostazol
• Cisapride
• Citalopram
• Clarithromycin
• Clopidogrel
• Cobimetinib
• Cocaine
• Codeine
• Codergocrin
• Caffeine
• Copanlisib
• Daclatasvir
• Dapsone
• Deflazacort
• Dexamethasone
• Dextromethorphan
• Diazepam (weak) (benzodiazepine)
• Diltiazem
• Docetaxel
• Domperidone
• Doxepin
• Efavirenz
• Elbasvir/Grazoprevir
• Eliglustat
• Eplerenone
• Ergotamine
• Erythromycin
• Escitalopram
• Esomeprazole
• Estradiol
• Felodipine
• Fentanyl
• Finasteride
• Flibanserin
• Haloperidol
• Hydrocortisone
• Ibrutinib
• Idelalisib
• Imatinib
• Indinavir
• Irinotecan
• Isavuconazole
• Ivabradine
• Caffeine
• Cocaine
• Lansoprazole
• Lenvatinib
• Lercanidipine
• Levateylmethadol
• Lidocaine
• Lovastatin
• Methadone
• Midazolam
• Naldemedin
• Naloxegol
• Nateglinide
• Nelfinavir
• Neratinib
• Netupitant/Palonosetron
• Nevirapine
• Nifedipine
• Nisoldipine
• Nitrendipine
• Olaparib
• Omeprazole
• Ondansetron
• Osimertinib
• Paclitaxel
• Palbociclib
• Panobinostat
• Pantoprazole
• Pimavanserin
• Pimozide
• Progesterone
• Propranolol
• Quetiapine
• Reboxetine¹²
• Regorafenib
• Ribociclib
• Risperidone
• Ritonavir
• Rolapitant
• Romidepsin
• Salbutamol
• Salmeterol
• Saquinavir
• Selexipag
• Sildenafil
• Simvastatin
• Sirolimus
• Sonidegib
• Sorafenib
• Sunitinib
• Suvorexant
• Tacrolimus
• Tamoxifen
• Telaprevir
• Telithromycin
• Temsirolimus
• Terfenadine
• Testosterone
• Tramadol
• Trazodone
• Valbenazine
• Velpatasvir
• Vemurafenib
• Venetoclax
• Venlafaxine
• Verapamil
• Vincristine
• Voriconazole
• Zaleplon
• Ziprasidone
• Zolpidem

8.3.1.3.2. CYP3A4 inhibitors¶

Inhibitor: Inhibits CYP3A4, so that less CYP3A4 degradation effect is available. This can lead to active ingredients being broken down too slowly. There is a risk of overdose and increased side effects.
Strong inhibitors can cause:
up to over 5-fold increase in plasma AUC values
up to over 80 percent decrease in clearance

• Acetazolamide
• Amiodarone
• Anastrozole
• Apomorphine
• Aprepitant (strong)
• Atazanavir (strong)
• Atomoxetine
• Atorvastatin (strong)
• Valerian¹³
• Berber (strong?)¹⁴
  • Different view¹⁵
• Boceprevir
• Clarithromycin (strong) (antibiotic, macrolide)¹⁶¹³
• Chloramphenicol (antibiotic)¹³
• Cimetidine
• Ciprofloxacin
• Clonazepam (strong) (benzodiazepine)
• Cobicistat
• Delavirdin
• Diltiazem (strong)¹⁶
• Erythromycin (strong) (antibiotic, macrolide)¹⁶¹³
• Esomeprazole
• Fluconazole (antimycotic)¹³
• Fluoxetine (weak to moderate)¹⁶
• Fluvoxamine (weak to moderate)¹⁶
• Turmeric¹³
• Gestodene
• Ginseng¹³
• Grapefruit (strong)¹⁶¹³
• Idelalisib (strong)
• Imatinib
• Indinavir (strong)
• Itraconazole (strong) (antifungal)¹³
• Ketoconazole (strong) (antifungal agent)¹⁶¹³
• Lesinurad
• Mibefradil
• Mifepristone
• Nefazodon (strong)
• Nelfinavir (strong)
• Netupitant/Palonosetron
• Norfloxacin
• Omeprazole
• Pantoprazole
• Paritaprevir
• Regorafenib
• Star fruit
• Telaprevir
• Telithromycin (antibiotic, macrolide)¹³
• Verapamil
• Voriconazole

8.3.1.3.2.1. CYP3A4 inhibitors and guanfacine¶

Strong CYP3A4 inhibitors increase the blood level of guanfacine after the start of administration, weak and moderate CYP3A4 inhibitors may do so.¹⁶

While the package leaflet recommends halving the dose of guanfacine with concomitant administration of CYP3A4 inhibitors, halving the dose does not appear to be sufficient when taking augmenting antipsychotics.¹⁶ Avoiding CYP3A4 inhibitors appears to be advisable when taking guanfacine at the same time.

Grapefruit juice should always be avoided when taking psychiatric medication.¹⁶

8.3.1.3.3. CYP3A4 inducers¶

Inducer: Enhances CYP3A4 so that an increased CYP3A4 degradation effect is available. This can cause active ingredients to be broken down too quickly.

• Aminogluthetimide
• Alcohol (ethanol)
• Amprenavir (strong)
• Aprepitant
• Armodafinil (weak)¹⁶
• Azatadine
• Barbiturates
• Brigatinib
• Carbamazepine (strong) (anticonvulsant)¹³¹⁶
• Quinolones¹³
• Dexamethasone¹³
  • Not: Prednisone¹³
• Efavirenz
• Enzalutamide
• Ethanol
• Glucocorticoids
• Ginger¹³
• St. John’s wort (St. John’s wort) (weak)¹³¹⁶
• Garlic¹³
• Licorice¹³
• Modafinil (weak)¹³¹⁶
• Nevirapine
• Oxcarbazepine (weak) (anticonvulsant)¹³¹⁶
• Phenobarbital (strong)¹³¹⁶
• Phenytoin (strong) (anticonvulsant)¹³¹⁶
• Pioglitazone
• Ribociclib (strong)
• Rifabutin
• Rifampin / Rifampicin (strong)¹³¹⁶
• Ritonavir (strong)
• Saquinavir (strong)
• St. John’s word (weak)¹³¹⁶
• Telithromycin (strong)
• Topiramate (weak)¹⁶
• Troglitazone

8.3.1.3.3.1. CYP3A4 inducers and guanfacine¶

Strong CYP3A4 inducers reduce the blood level of guanfacine within 2 to 3 weeks after the start of administration, while weak and moderate CYP3A4 inducers can do the same.¹⁶ Conversely, the guanfacine level rises again 2 to 3 weeks after discontinuation of CYP3A4 inducers.

While the package leaflet recommends doubling the dose of guanfacine with concomitant administration of CYP3A4 inducers, augmenting ingestion of phenobarbital required a 5-fold dose in one individual case.¹⁶ Avoiding strong CYP3A4 inducers appears to be advisable when taking guanfacine at the same time.

8.3.1.3.4. Other interactions of guanfacine¶

Valproate is said to show increased plasma levels when taken in parallel with guanfacine.¹⁷

Guanfacine and clonidine should be antagonized by tricyclic antidepressants and phenothiazines.¹⁸

Simultaneous use of beta-blockers or sudden discontinuation of guanfacine can lead to a hypertensive reaction.¹⁸