Dear reader of ADxS.org, please excuse the disruption.

ADxS.org needs about $63500 in 2024. In 2023 we received donations of about $ 32200. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2024 would be over after a few days. This donation request is displayed 23,000 times a week, but only 75 people donate. If you find ADxS.org useful, please take a minute and support ADxS.org with your donation. Thank you!

Since 01.06.2021 ADxS.org is supported by the non-profit ADxS e.V..

$18094 of $63500 - as of 2024-04-30
28%
Header Image
CYP3A4 Metabolizing enzyme

Sitemap

CYP3A4 Metabolizing enzyme

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 of 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. Although 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 administration of phenobarbital required a 5-fold dose in a single 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


  1. 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

  2. Keiner (2015): Gendermedizin – Dosisanpassung selten erforderlich. Pharmazeutische Zeitung.

  3. 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 Nov 1:1-32. doi: 10.1080/00498254.2022.2141151. PMID: 36317558.

  4. Werk AN, Cascorbi I (2014): Functional gene variants of CYP3A4. Clin Pharmacol Ther. 2014 Sep;96(3):340-8. doi: 10.1038/clpt.2014.129. PMID: 24926778. REVIEW

  5. 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.

  6. GeneCards.org POR

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. Maucher (2019): CYP3A4. Gelbe Liste

  12. Kirsch (2005): Phäno- und Genotypisierung zur Abwehr von unerwünschten Arzneimittelwirkungen am Beispiel zweier Antidepressiva, Dissertation

  13. CYP3A4 bei DocCheck Flexikon, abgerufen am 23.12.19

  14. 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.

  15. 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.

  16. 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.

  17. Ambrosini, Sheikh (1998): Increased plasma valproate concentrations when coadministered with guanfacine. J Child Adolesc Psychopharmacol. 1998;8(2):143-7. doi: 10.1089/cap.1998.8.143. PMID: 9730080.

  18. Markowitz, Patrick (2001): Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet. 2001;40(10):753-72. doi: 10.2165/00003088-200140100-00004. PMID: 11707061. REVIEW

Diese Seite wurde am 05.04.2024 zuletzt aktualisiert.