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CYP3A4 Metabolizing Enzyme

CYP3A4 Metabolizing Enzyme

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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 commonly used drugs, making it the most important CYP450 enzyme.
The following relevant ADHD medications are metabolized via CYP3A4:

  • Guanfacine

CYP3A4 is expressed in the gastrointestinal tract and the liver and is particularly involved in the metabolism of large lipophilic molecules (e.g., endogenous steroids). Among the most potent inhibitors of this isoenzyme are the azole antifungal ketoconazole and the protease inhibitor ritonavir.

CYP3A4 is more active in women than in men,2 so women may require higher doses of medications metabolized by CYP3A4 than men.
In addition, there are drug interactions that either increase (inducers) or decrease (inhibitors) the enzymatic 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

1. CYP3A4 gene variants influence the rate of metabolism

The effects of genetic variants on metabolism by CYP3A4 appear to be weaker than those observed with other CYP 450 enzymes.

The following CYP3A4 gene variants have been reported to affect metabolism:4

  • I118V: reduced activity
  • R130Q: no protein formation
  • T185S on allele 16A: reduced protein synthesis 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 tacrolimus clearance / unchanged activity / increased activity
  • T363M: reduced protein production and activity
  • L373F: reduced protein production and activity
  • P416L: no protein formation
  • 488-frameshift: low midazolam clearance / no protein formation
  • intron 6 C15389T reduced activity

2. POR gene variants influence the rate of CYP3A4 metabolism

In addition to CYP3A4 gene variants, the efficacy of CYP3A4 metabolism is influenced by gene variants of the POR gene (cytochrome P450 oxidoreductase, NADPH P450 oxidoreductase, CPR).5 The enzyme encoded by POR is required for electron transfer from NADP to cytochrome P450 in microsomes and mediates electron transfer to heme oxygenase and cytochrome B5.6 Each POR gene variant affects each CYP differently. The effect on CYP2D6 cannot therefore be extrapolated to other CYP enzymes.
POR (CPR) decreases with age and was 27% lower in men over 45 than in men under 45. Since CYP levels also decreased, the ratio remains roughly the same.7

To date, there have been no studies on the effects on ADHD medications metabolized by CYP3A4. Therefore, estimates can only be made based on the effects on other medications metabolized by CYP3A4.

Studies, particularly those conducted by the research group led by Flück et al., examined the effect of various gene variants on the metabolism of CYP2D68, CYP3A45, CYP17A19, and CYP19A110.
As the work by Flück et al. shows, the effects of POR gene variants on the activity of various CYP 450 enzymes are not identical, but are roughly comparable. Only Q153R deviates significantly with regard to CYP17A1. From this, we can roughly infer what influence the POR gene variants might have on CYP 450 enzymes that have not been studied.

Gene variant as a percentage of the wild-type CYP2D6 as a percentage of the wild-type CYP3A4 as a percentage of the wild-type CYP17A1 as a percentage of the wild-type 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 that POR had only a minor effect on the efficiency of CYP3A4 metabolism (in this case, of midazolam).7

The POR gene variant can be identified through a laboratory test.

3. CYP3A4 Substrates / CYP3A4 Inhibitors / CYP3A4 Inducers

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

This list—like all information on ADxS.org—is not intended for personal therapeutic use. Although we make every effort to gather all relevant information, the list is nonetheless incomplete. Errors cannot be ruled out. Please consult your doctor or pharmacist.

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
  • Cyclosporine
  • Cilostazol
  • Cisapride
  • Citalopram
  • Clarithromycin
  • Clopidogrel
  • Cobimetinib
  • Cocaine
  • Codeine
  • Codergocrin
  • Caffeine
  • Copanlisib
  • Daclatasvir
  • Dapsone
  • Deflazacort
  • Dexamethasone
  • Dextromethorphan
  • Diazepam (mild) (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

3.2. CYP3A4 inhibitors

Inhibitor: Inhibits CYP3A4, resulting in reduced CYP3A4 metabolic activity. This can cause active ingredients to be metabolized too slowly. There is a risk of overdose and increased side effects.
Strong inhibitors can cause:
an increase of more than fivefold in plasma AUC values
a decline of more than 80 percent in clearance

  • Acetazolamide
  • Amiodarone
  • Anastrozole
  • Apomorphine
  • Aprepitant (strong)
  • Atazanavir (strong)
  • Atomoxetine
  • Atorvastatin (high-strength)
  • Valerian13
  • Berber (strong?)14
    • different view15
  • Boceprevir
  • Clarithromycin (strong) (antibiotic, macrolide)1613
  • Chloramphenicol (antibiotic)13
  • Cimetidine
  • Ciprofloxacin
  • Clonazepam (strong) (benzodiazepine)
  • Cobicistat
  • Delavirdine
  • Diltiazem (strong)16
  • Erythromycin (strong) (antibiotic, macrolide)1613
  • Esomeprazole
  • Fluconazole (antifungal)13
  • Fluoxetine (mild to moderate)16
  • Fluvoxamine (mild to moderate)16
  • Goldenseal13
  • Gestodene
  • Ginseng13
  • Grapefruit (strong)1613
  • Idelalisib (strong)
  • Imatinib
  • Indinavir (strong)
  • Ginger13
  • Itraconazole (strong) (antifungal)13
  • Ketoconazole (strong) (antifungal)1613
  • Lesinurad
  • Mibefradil
  • Mifepristone
  • Nefazodone (strong)
  • Nelfinavir (strong)
  • Netupitant/Palonosetron
  • Norfloxacin
  • Omeprazole
  • Pantoprazole
  • Paritaprevir
  • Regorafenib
  • Star fruit
  • Telaprevir
  • Telithromycin (antibiotic, macrolide)13
  • Verapamil
  • Voriconazole

3.2.1. CYP3A4 Inhibitors and Guanfacine

Strong CYP3A4 inhibitors increase blood levels of guanfacine after treatment initiation; weak and moderate CYP3A4 inhibitors may also cause this effect in some cases.16

While the package insert recommends halving the guanfacine dose when taken concomitantly with CYP3A4 inhibitors, halving the dose does not appear to be sufficient when taken in combination with antipsychotics.16 It appears advisable to avoid CYP3A4 inhibitors when taking guanfacine concurrently.

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

3.3. CYP3A4 Inducers

Inducer: Enhances CYP3A4 activity, resulting in increased CYP3A4 metabolism. This can cause active ingredients to be metabolized too quickly.

  • Aminoglutethimide
  • Alcohol (Ethanol)
  • Amprenavir (strong)
  • Aprepitant
  • Armodafinil (mild)16
  • Azatadin
  • Barbiturates
  • Brigatinib
  • Carbamazepine (strong) (anticonvulsant)1316
  • Quinolones13
  • Dexamethasone13
    • not: prednisone13
  • Efavirenz
  • Enzalutamide
  • Ethanol
  • Glucocorticoids
  • St. John’s wort (St. John’s wort) 1316(stark) (Official Overview, E 4)17
  • Garlic13
  • Licorice13
  • Modafinil (mild)1316
  • Nevirapine
  • Oxcarbazepine (mild) (anticonvulsant)1316
  • Phenobarbital 13 16 (mild) (Regulatory overview, E 4) 17
  • Phenytoin (strong) (anticonvulsant)1316
  • Pioglitazone
  • Ribociclib (strong)
  • Rifabutin
  • Rifampin / Rifampicin (strong)1316
  • Ritonavir (strong)
  • Saquinavir (strong)
  • St. John’s wort (mild)1316
  • Telithromycin (strong)
  • Topiramate (mild)16
  • Troglitazone

3.3.1. CYP3A4 Inducers and Guanfacine

Strong CYP3A4 inducers reduce blood levels of guanfacine within 2 to 3 weeks after starting treatment; weak and moderate CYP3A4 inducers may also cause this effect.16 Conversely, guanfacine levels rise again 2 to 3 weeks after discontinuing CYP3A4 inducers.

While the package insert recommends doubling the guanfacine dose when administered concomitantly with CYP3A4 inducers, in one individual case, the addition of phenobarbital required a 5-fold increase in the dose.16 It appears advisable to avoid strong CYP3A4 inducers when taking guanfacine concomitantly.

3.4. Other Drug Interactions with Guanfacine

Valproate is reported to result in elevated plasma levels when taken concurrently with guanfacine.18

Guanfacine and clonidine are believed to be antagonized by tricyclic antidepressants and phenothiazines.19

Concomitant use of beta-blockers or sudden discontinuation of guanfacine may lead to a hypertensive reaction.19

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  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. U.S. Food and Drug Administration: Healthcare Professionals: FDA’s Examples of Drugs that Interact with CYP Enzymes and Transporter Systems. Stand 2026 May 29. ↥ ↥

  18. 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. ↥

  19. 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 ↥ ↥