UPDATED: 24 May 2024
This post was written primarily for people who are relatively immune to the effects of opioids because if they ever land in hospital or need pain meds, they might not be believed so they need to know exactly what type of drug metaboliser (the process of enzymatic catabolism and anabolism) they are and there is a test available (discussed later) but I suggest that you read [the metabolism of food and drugs](
https://www.reddit.com/r/Drugs/s/9YUt8oIAwu) first.
* **The Four Metaboliser Types**
Genes and enzymes help determine our individual rate of metabolism, which varies from person to person. Depending on your genetic profile, you may process some medications too quickly, or others, too slowly, which can both cause complications.
Research has found that people fall into one of four general metabolizer types.
• **Poor Metaboliser**: Medication is broken down very slowly. May experience side effects at standard doses. About 5% of the population.
The **CYP3A4 gene** and the **Slow Metaboliser**: People having at least one °22 allele of the CYP3A4 gene (CYP3A4 °22/°22 or CYP3A4°1/°22) are said to be **Poor Metabolisers**.
• **Intermediate Metaboliser**: Slow rate of metabolism. May have too much medication at standard doses, potentially causing side effects. About 10% of the population.
• **Extensive Metaboliser**: Normal rate of metabolism. Has normal amount of medication at standard doses. About 82% of the population.
• **Ultrarapid Metaboliser**: Medication is rapidly broken down. Medication may be removed from a patient’s system too quickly to provide symptom relief. About 3% of the population.
If they're an **Ultrarapid Metaboliser** they should discuss **CYP450 testing** as it could literally save them a world of pain.
Codeine and Tramadol are metabolised in the liver to their active forms (Codeine to Morphine and Tramadol to M1 or O-desmethyl-tramadol) by an enzyme called cytochrome P450 **isoenzyme 2D6 (CYP2D6)**.
Genetic polymorphism in the CYP2D6 gene results in significant variation of this enzyme, in the ability of individuals to metabolise codeine to morphine.
Ultra-rapid metabolizers rapidly clear medications and thereby can minimize or eliminate the therapeutic response from active parent opioids.
Individuals with ultrarapid or limited enzymatic capacity can have either an increased risk of adverse effects from higher than expected systemic concentrations of an active compound (either parent or metabolite) or be prone to **inadequate analgesic responses** when an active opioid does not become bioavailable.
For proof, you should undergo a **Cytochrome P450 test** which uses a blood sample to determine an individual's required dosage of identified drugs that are metabolized by the two enzymes.
The cytochrome P450 **gene (CYP) enzymes** are membrane-bound hemoproteins (in the red blood cells) that play a pivotal role in the detoxification of xenobiotics (foreign substances), cellular **metabolism** and homeostasis.
They are found mainly in the liver but exist all throughout the body as they are detectable in blood.
Phase 1 metabolism of opioids mainly involves the **CYP3A4/5, CYP2C8/9 and CYP2D6** enzymes.
"It is unknown just how prevalent severe intractable pain patients with CYP 450 defects who **require high dose opioid therapy** may be compared to the general, chronic pain population, but it is probably a small percentage."
The *lower* innate **oral bioavailability** of the drug, the *greater the possible increase* in systemic drug concentration.
The CYP2D6 enzyme is the primary activator of **codeine, oxycodone, hydrocodone, and tramadol**, which are termed prodrugs because their metabolites are more potent analgesics than the parent molecule.
Some drugs are metabolized by both CYP2D6 and CYP3A4, but because CYP2D6 is the enzyme responsible for producing the active metabolites, inhibition of CYP3A4 activity does not appear to be as important as CYP2D6.
Drugs and compounds which **inhibit** or antagonize the biosynthesis or actions of CYTOCHROME P-450 **CYP2D6** include a selective serotonin reuptake inhibitor used to treat major depressive disorder, bulimia, OCD, premenstrual dysphoric disorder, panic disorder, and bipolar I, some are listed below.
Fluoxetine (Prozac),
Bupropion (Wellbutrin,
Cinacalcet,
Quinidine,
Clozapine,
Haloperidol,
Paroxetine,
Duloxetine (Cymbalta),
Fluvoxamine,
Halofantrine,
Propafenone,
Propranolol,
Amiodarone,
Aripiprazole (Abilify),
Berberine,
Celecoxib,
Cimetidine,
Cisapride,
Diphenhydramine (Benadryl),
Escitalopram,
Loratadine,
Metoclopramide,
Metoprolol,
Midostaurin
Drugs metabolized mainly by CYP2B6 include artemisinin, **bupropion, cyclophosphamide, efavirenz, ketamine, and methadone**. CYP2B6 is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity.
The inhibition of CYP3A4 activity by green tea extracts could increase the plasma concentrations of midazolam.
* **The metabolism of Tramadol**
Tramadol is a centrally acting μ-opioid receptor agonist and **SNRI** (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine.
It's metabolism demonstrates how the **CYP2D6** system is more significant because its anabolism to the **active metabolites** but normally most opioids are metabolised by CYP3A4 and this enzyme has a **high risk of drug-drug interactions**.
Tramadol has a very **high oral bioavailability** of between 70-90% and is metabolised by **CYP2D6** into **pharmacologically active O-desmethyltramadol** (200 times more affinity than tramadol for opiate receptors) 👍 ✔️ but when metabolised by the **CYP2B6 and CYP3A4** enzymes it also becomes the **inactive** N-desmethyltramadol which is no fun.
* **Grapefruit as P450 inhibitors**
A whole Grapefruit or it's juice (200~250 ml) will boost serum levels will increase the effects of **most opioids and some benzodiazepines** but give it at least **30 minutes** to kick in first (see further down for predosing considerations).
Biopsies revealed that higher CYP3A4 levels before ingesting grapefruit juice resulted in greater decrease in enzyme levels and greater increase in oral drug bioavailability after consumption of the juice.
Grapefruit can **potentiate by up to 47% within 4 hours and for up to 24-72 hours** so be careful !
* **Circumstances of Grapefruit Consumption**
Indeed, a single usual amount (i.e., 200–250 mL juice or a whole grapefruit) has sufficient potency to cause a pertinent pharmacokinetic interaction.
For example, felodipine combined with such a quantity of grapefruit had an average systemic drug concentration that was 3-fold that seen with water.
With twice the amount of grapefruit, there was only a modestly greater increase in the systemic concentration of felodipine, showing that a near-maximal pharmacokinetic interaction had already occurred with the consumption of the single quantity.
With repeated ingestion of grapefruit (250 mL of juice, 3 times/d for 6 d), a single dose of felodipine increased to 5 times the systemic concentration seen with water, suggesting that frequent consumption of a usual quantity daily augmented the pharmacokinetic effect moreso than the lone quantity.
The interval between the ingestion of grapefruit and the adminstration of the interacting drug has some effect on pharmacokinetics. For example, a single glass (200 mL) of grapefruit juice ingested within 4 hours before felodipine produced the maximal pharmacokinetic interaction.
Thereafter, an increased interval between ingesting the 2 substances slowly decreased the size of the effect — an interval of 10 hours produced an effect that was 50% of the maximum, and an interval of 24 hours produced an effect that was 25% of the maximum.
Thus, a modest solitary quantity of grapefruit can have sufficient duration of action to affect interacting drugs that are administered once daily at any time during the dosing interval.
Furthermore, repeated ingestion of grapefruit (200 mL of juice, 3 times/d for 7 d) doubled the size of the interaction for 24 hours, consistent with a cumulative inhibitory action.
* **Opioids affected by Grapefruit**
Grapefruit also affects the metabolism by increasing the analgesia and side effects of Hydrocodone, Oxycodone, Oxymorphone, Morphine, Diamorphine, Hydromorphone, Methadone, Fentanyl, Kratom, Dextromethorphan and *minimally*, Buprenorphine.
Grapefruit does not potentate both Tramadol and Codeine due to it mainly working on CYP3A4.
This is thoroughly studied in:
* Opioid Metabolism and Effects of Cytochrome P450
https://academic.oup.com/painmedicine/article/10/suppl_1/S20/1914905**Benzodiazepines affected by Grapefruit**
Benzodiazepines' beneficial properties and side effects can be altered by agents that either accelerate or delay its metabolism.
Grapefruit affects the metabolism of many drugs, including Alprazolam (Xanax), Diazepam (Valium), Triazolam (Halcion) Midazolam (Versed), Flurazepam (Dalmane) and *minimally*, Clonazepam (Klonopin).
* **Key points**
Currently, more than 85 drugs have the possibility of interacting with grapefruit; of these drugs, 43 have interactions that can result in serious adverse effects.
Drugs that interact with grapefruit have all of the following characteristics: they are administered orally, they have very low to intermediate absolute bioavailability, and they are metabolized by the cytochrome P450 3A4 enzyme (CYP3A4).
All sources of grapefruit and certain related citrus fruits can irreversibly inhibit CYP3A4 in the gastrointestinal tract; to prevent this interaction, affected drugs should not be consumed with any of these fruits during the treatment period, or noninteracting alternative medications should be prescribed.
Older patients have the greatest possibility of ingesting grapefruit and interacting medications and are the most vulnerable to the adverse clinical consequences.
* **What other substances might I be interested in what are other enzymatic potentiators ?**
I recommend Turmeric/Curcumin as the best CYP3A4 Inhibitor because it's eliminated within 12 hours and it reaches at least 90% full inhibition, when you consider the information below.
* What enzymes were used to metabolise them ?
THC is metabolized into other molecules by CYP2C and CYP3A in the liver.
Modafinil undergoes hepatic metabolism via multiple pathways, including CYP3A4.
* What are their effects on metabolising other drugs ?
THC competitively inhibited CYP1A2, CYP2B6, CYP2C9, and CYP2D6; CBD competitively inhibited CYP3A4, CYP2B6, CYP2C9, CYP2D6, and CYP2E1.
> In vitro, **modafinil** was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes.
> These data support consideration of the risk of clinically relevant metabolic drug–drug interactions perpetrated by **modafinil** when this drug is co‐administered with drugs that are primarily cleared by CYP2C19 (single modafinil dose or steady state modafinil dosing) or CYP3A4 (steady state modafinil dosing only) catalysed metabolic pathways.
* Turmeric
> Curcumin is a polyphenolic component in turmeric that inhibits CYP1A2, CYP2B6, CYP2C9, CYP2D6, and CYP3A4. **CYP2C9 being the most inhibited**.
> Curcumin at 5 and 10 µM significantly inhibited the activity of CYP3A4 by 93% and 90%, respectively.
> Curcumin stays in your system for 6-8 hours, undetectable after 12 hours.
> The safe dose of Curcumin is 0.3 mg/kg/day
* Piperine
> Inactivation of CYP3A subfamily members (mainly CYP3A4 and CYP3A5)
> Safe dose of piperine ranging from 5–20 mg per day
> Half-life (t1/2) of piperine in humans is about 13.2–15.8 h, suggesting that it has a long elimination time in the human body.
* **Some of the references**
https://pubmed.ncbi.nlm.nih.gov/17990736/ https://www.jpsmjournal.com/article/S0885-3924(12)00492-7/fulltext* CYP2D6 polymorphism and tramadol
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/o-desmethyltramadol#:~:text=Tramadol%20is%20metabolized%20by%20CYP2D6,%2Ddesmethyltramadol%20(inactive%20metabolite).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657965/#:~:text=Human%20cytochrome%20P450%20(CYP)%20enzymes,%2C%20cellular%20metabolism%2C%20and%20homeostasis.
* Cytochrome P450 Enzymes and Drug Metabolism in Humans
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704133/#:~:text=Phase%201%20metabolism%20of%20opioids,risk%20of%20drug%2Ddrug%20interactions.
* Grapefruit–medication interactions: Forbidden fruit or avoidable consequences?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589309/#:~:text=Indeed%2C%20a%20single%20usual%20amount,cause%20a%20pertinent%20pharmacokinetic%20interaction.&text=For%20example%2C%20felodipine%20combined%20with,fold%20that%20seen%20with%20water.
● Addendum / reference:
CYP3A4 Gene – The different metaboliser types - the Slow Metabolisers: People having at least one *22 allele of the CYP3A4 gene (CYP3A4 *22/*22 or CYP3A4*1/*22) are said to be poor metabolizers.
* How The CYP3A4 Gene Influences Detoxification
Last updated: November 12, 2021
https://www.xcode.life/genes-and-detox/how-the-cyp3a4-gene-influences-detoxification/#:~:text=CYP3A4%20Gene%20%E2%80%93%20The%20Different%20Metabolizer%20Types,-There%20are%20over&text=Slow%20Metabolizers%3A%20People%20having%20at,said%20to%20be%20poor%20metabolizers.