Represents the largest proportion of cytochromes with 29 % (liver). Metabolizes about 40 to 50 % of the common drugs. As of 2001, no clear genotype-phenotype correlation was known.
At relevant ADHD drugs is metabolized via CYP3A4:
CYP3A4 is expressed in the gastrointestinal tract and 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, so women may require a higher dose than men.
Further, there are 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.
22.214.171.124. CYP3A4 substrates/inhibitors/inducers
The presentation is largely based on the compilation by Maucher (2019) and has been expanded and supplemented by us.
*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. *
126.96.36.199.1. CYP3A4 substrates
Substrate: binds to (here: is metabolized by) CYP3A4.
Quinine (tonic water, bitter lemon)
Diazepam (weak) (benzodiazepine)
188.8.131.52.2. CYP3A4 inhibitors
Inhibitor: Inhibits CYP3A4 so that less CYP3A4 degradation effect is available. This may result in active ingredients being broken down too slowly. There is a risk of overdose and increased side effects.
Strong inhibitors can cause:
up to more than 5-fold increase in plasma AUC levels
to over 80 percent decrease in clearance
- Aprepitant (strong)
- Atazanavir (strong)
- Atorvastatin (strong)
- Clarithromycin (strong) (antibiotic, macrolide)
- Chloramphenicol (antibiotic)
- Clonazepam (strong) (benzodiazepine)
- Diltiazem (strong)
- Erythromycin (strong) (antibiotic, macrolide)
- Fluconazole (antifungal)
Fluoxetine (weak to moderate)
- Fluvoxamine (weak to moderate)
- Idelalisib (strong)
- Indinavir (strong)
- Itraconazole (strong) (antifungal)
- Ketoconazole (strong) (antifungal)
- Nefazodone (strong)
- Nelfinavir (strong)
- Telithromycin (antibiotic, macrolide)
184.108.40.206.2.1. CYP3A4 inhibitors and guanfacine
Strong CYP3A4 inhibitors increase blood levels of guanfacine after initiation; weak and moderate CYP3A4 inhibitors may do so if appropriate.
While the package insert recommends halving the guanfacine dose when CYP3A4 inhibitors are administered concomitantly, halving does not appear to be sufficient when antipsychotics are taken augmentatively. Avoidance of CYP3A4 inhibitors appears to be recommended when guanfacine is taken concomitantly.
Grapefruit juice should always be avoided when taking psychiatric medications.
220.127.116.11.3. CYP3A4 inducers
Inducer: Enhances CYP3A4 so that an enhanced CYP3A4 degradation effect is available. This may cause drugs to be degraded too rapidly.
- Amprenavir (strong)
- Armodafinil (weak)
- Carbamazepine (strong) (anticonvulsant)
- **St. John’s wort **(St. John’s wort) (weak)
- Modafinil (weak)
- Oxcarbazepine (weak) (anticonvulsant)
- Phenobarbital (strong)
- Phenytoin (strong) (anticonvulsant)
- Ribociclib (strong)
- Rifampin / Rifampicin (strong)
- Ritonavir (strong)
- Saquinavir (strong)
St. John’s word (weak)
- Telithromycin (strong)
- Topiramate (weak)
18.104.22.168.3.1. CYP3A4 inducers and guanfacine
Strong CYP3A4 inducers decrease blood levels of guanfacine within 2 to 3 weeks after initiation; weak and moderate CYP3A4 inducers may do so. Conversely, guanfacine levels increase again 2 to 3 weeks after discontinuation of CYP3A4 inducers.
While the package insert recommends doubling the guanfacine dose with concomitant administration of CYP3A4 inducers, augmenting phenobarbital in a single case required a 5-fold dose. Avoidance of potent CYP3A4 inducers seems advisable when guanfacine is taken concomitantly.
22.214.171.124. Other interactions of Guanfacin
Valproate is reported to show increased plasma levels when taken concomitantly with guanfacine.
Guanfacine and clonidine are thought to be antagonized by tricyclic antidepressants and phenothiazines.
Concomitant use of beta-blockers or sudden discontinuation of guanfacine may result in a hypertensive response.