Cytochrome P450 Puns

Just curious what has worked for you?

With Bacopa, the usual fear is that, by inhibiting cytochrome P450, it can prevent the metabolization and thus the elimination of certain antidepressants and anti-psychotics, leading to a potential overdose. [1] [2]

[1] See: "Bacopa Side Effects" https://www.superfoods-scientific-research.com/medicinal-herbs/bacopa-side-effects.html

[2] PUBMED: Inhibition of human cytochrome P450 enzymes by Bacopa monnieri standardized extract and constituents https://pubmed.ncbi.nlm.nih.gov/24566323/

However, I found nothing regarding bacopa and xanax (generic name: alprazolam) despite looking for articles or threads on the subject via numerous search engines (Google, DuckDuckGo, etc.). However, it is my personal experience that bacopa prevents xanax from working at all (which I take on rare ocassions for chest pains and panic attacks).

Alprazolam (xanax) is metabolized by Cytochrome P450 into alpha-hydroxy alprazolam (alpha-OHALP, pharmacologically more active) and 4-hydroxy alprazolam (4-OHALP, pharmacologically less active). [2]

[2] https://pubmed.ncbi.nlm.nih.gov/12196913/

I've been taking Bacopa for a few days now, and I just tried taking 0.5mg of xanax for an acute case of anxiety, and I felt nothing. Took a second 0.5mg of xanax an hour later. Still felt NOTHING.

So I suppose I'll need to discontinue Bacopa despite its blood flow improving and neuroprotective effects against the type of damage benzodiazipines can do to the brain. Luckily, I take other neuroprotective supplements (like Gingko Biloba and Acetyl-L-Carnitine) that do not interfere with Cytochrome P450 activity.

So, just a warning: if you are prescribed xanaz (i.e. alprazolam, or any other type of benzodiazipine for that matter) for panic attacks or for chest pains (angina) resulting from hypoxia (lack of blood flow to the heart, which can be induced by extreme stress or anxiety), you likely want to avoid taking Bacopa as it will interfere with your metabolization of the drug. It may still work to some degree, I don't know, perhaps in a few hours I'll feel it kick in. I'll report back later with any changes.

But yes, two hours later, and I can't feel it and my anxiety is still here an hour later and my chest pains had to be subdued with nitroglycerin. So, yes, if you take any other prescription drug that

Introduction
Hello fellow drug nerds.

I have been enjoying the content of this forum for a while and decided to contribute with some of my own research. Below is what I have compiled so far.

If you have any additional or corrective knowledge about these processes, feel free to join in and help create an accurate understanding of how the enzyme inhibition works and practical pointers to safe use.

The Grapefruit Effect
Grapefruits contain the compounds furanocoumarins, which inhibits the CYP3A4 enzyme, which improve the availability of dissociatives, stimulants, sedatives and many other recreational and non-recreational compounds.

The furanocoumarins are supposedly found in the greatest concentration in the juice of the grapefruit, but final confirmation to this fact is needed.

The lower the bioavailability of any given drug, the higher the increase of the drug will be. The inhibition of the CYP3A4 enzyme leads to a higher systemic concentration (more drug actively available to create effect in body) as the chemical processes that usually break it down, become considerably slowed by the lack of enzymes.

This effectively allows users of the grapefruit effect to lower their doses of certain substances, as potency will be increased. The effect will, however differ, as the general activity of the CYP3A4 enzyme varies broadly in people (up to a 40-fold difference). Which explains the various reactions seen. It is therefore advisable to proceed with caution and stay attentive to past and present patterns in personal metabolism.

To inhibit the CYP3A4 enzyme, a 200 g of grapefruit should suffice to create a "clinically relevant" inhibitory effect and it does not matter if the grapefruit is white or red (although common misconceptions suggests otherwise).

The inhibition of the CYP3A4 enzyme occurs in the intestine, but not the liver, which seem to suggest that it specifically applies to the oral dosing route. If you have knowledge to suggest that the effect also takes place in the liver at a certain concentration, feel free to chime in.

As the one who have severe drug-metabolism malfunction, I found some information might related with our symptoms. I'm not sure I'm allowed to post link, so let me know if this is not allowed. Also, I'm not good at English, if i misunderstand any report, please let me know.

https://dmd.aspetjournals.org/content/24/10/1134.short

" Ciprofloxacin and norfloxacin significantly depressed the N-demethylation of erythromycin by CYP3A4 in human microsomes and by CYP3A2 in rat microsomes." " These studies in hepatic microsomes demonstrate that fluoroquinolones can decrease CYP3A- and CYP1A-mediated biotransformation by competitive inhibition and that they have the potential to cause drug interactions with agents metabolized by these enzymes."

This report said FQ antibiotics inhibit cytochrome P450 enzymes which used as drug metabolizer. Cytochrome p450 is an important enzyme in relation to drug liver metabolism and drug interaction. There are many active differences in this enzymes between races and individuals, resulting in differences in the function of drug metabolism, which can cause different drug effects for each person. While others can tolerate it well, and some have side effects from it. Major CYP450 enzymes involved in drug metabolism (CYP1A2, CYP2B6, CYP2C9 and CYP3A4) can be affected by FQ antibiotics, and this might be the reason why some floxie fellows such as me can't tolerate medicine.

https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers

This are list of Inhibitor and Inducer of Cytochrome P450 enzymes. FQ antibiotics are on the list of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 Inhibitors. Especially Ciprofloxacin and Norfloxacin, unluckily. I think FQ antibiotics inhibit our Cytochrome P450 enzymes with wrong way, then it affects our drug metabolism. That's why we cannot tolerate some supplements, or medicine such and flagyl, NSAIDs, Steroids, Antifungals, etc etc. It's side effects can be severe joint pain, tingling feeling all over the body, anxiety, acid reflux etc etc.

The key point is, our body's drug metabolism enzymes hurted by FQ, cannot metabolize medication through the liver well, so the residual toxicity from the medicine is remaining and floating in our blood, which i

I take Strattera 25mg, Wellbutrin 150mg & Brintellix 10mg daily.
(I suffer from dysthymic & anxiety disorder, OCPD, ADD and severe misophonia)

My doctor prescribes me this combination of drugs, but it seems a strange combination to me, considering many cytochrome 450 interactions.

Anyway, I recently changed the intake of vortioxetine from morning to just before bedtime. So before: I took all three pills together in the morning / After: Bupropion and Atomoxetine in the morning, Vortioxetine in the evening.

The mood changes that followed the days after this change lead me to suspect that there is a substantial difference in the resulting plasma concentrations of vortioxetine and its metabolites, after having changed the timing of intake.

So these are my questions:

• Could this be possible?

• Is it therefore advisable not to take drugs with a large P450 interaction together, but better spread as far apart as possible throughout the day?

• Is it even possible to obtain stable plasma concentrations when there are so many P450 interactions between the different drugs?

• Are there any studies about this subject?

• Has anyone already used this combination with his patients? (with good results?)

Cytochrome P450 CxnD exhibited C−S bond forming activity in chuangxinmycin biosynthesis, generating the unique tricyclic indole-S-hetero scaffold from thiol intermediates. Structural characterization of CxnD with a substrate analogue proposed a radical mechanism initiated by abstraction of the imino hydrogen atom or an electron from indole group of the substrate.

Abstract

Microbial sulfur-containing secondary metabolites show various biological activities, but the C−S bond-forming in their biosynthetic metabolism has not been thoroughly understood. Here, we present genetic, biochemical and structural characterization of a cytochrome P450 monooxygenase CxnD exhibiting C−S bond forming activity in S-heterocyclization of chuangxinmycin biosynthesis. In vivo and in vitro analyses demonstrated that CxnD generated an indole-fused dihydrothiopyran skeleton from a L-Trp-derived thiol intermediate. Furthermore, X-ray crystal structure of CxnD in complex with a substrate analogue and structure-based mutagenesis revealed intimate details of the substrate binding mode. A radical mechanism initiated by abstraction of the imino hydrogen atom or an electron from indole group of the substrate was proposed for CxnD, which provided valuable insights into the molecular basis for the intra-molecular C(sp2)−H thiolation by the P450 in chuangxinmycin biosynthesis.

https://ift.tt/2QPtCo0

Today’s fact of the day will address kava’s ability to inhibit (reduce function) of various enzymes known as cytochromes.

Cytochrome P450, also known as CYPs, are a family of enzymes that oxidize (break down) about 75-80% of all drugs in the body. These are important in the world of kava because kava, kava extract, and individual kavalactones have been shown in several studies to inhibit these enzymes to different degrees. When these enzymes are inhibited, whatever chemical which used that enzyme to metabolize will be slowed in its elimination, or at least in theory based on these papers.

https://preview.redd.it/fnj2pidvcdr61.jpg?width=2200&format=pjpg&auto=webp&s=12d7be6286a141120a6ba0b5f97866e3b3034d60

Most of the work today resides in the image attached. Attached is my attempt at taking these three studies and producing their results in a readable format. We’re using what’s known as IC50 values to denote the strength of inhibition of kava and fractions of kava. IC50 is defined as: a measure of the potency of a substance in inhibiting a specific biological or biochemical function [7]. Quite a number of natural products can inhibit these enzymes including grapefruit juice. In the attached diagram we see the reference values for grapefruit highlighted in yellow. These are the inhibition values you would see if you consumed grapefruit juice instead of kava. It’s worth it to note the inhibition values of grapefruit are much stronger than those of kava. The main two enzymes used in the vast bulk of elimination of pharmaceutical drugs are the enzymes CYP2D6 and CYP3A4. CYP2D6 was thought to be inhibited by kava, however these studies provide evidence that shows this may not be the case. CYP3A4, which accounts for roughly half of all drug metabolism has indeed shown inhibition in the presence of kava, and kava fractions.

What this means to the average kava drinker is that if you consume kava daily, you may want to watch out for pharmaceutical drugs which caution against the concurrent consumption of grapefruit juice. This warning is almost always printed on the side of the bottle. While kava may not be as strong of an inhibitor at these sites, it stands to reason that the compounding effect of consuming kava daily may indeed cause these inhibitory effects. This can cause these specific drugs to stay in your system for longer periods than intended, or cause their metabolites to stay in a specific form for a longer amount of time. Either

ADMET prediction of my query compounds show one of them isn’t a substrate or inhibitor of CYP2D6, 3A4, 1A2, 2C19, 2C9, but one of them is both a substrate and inhibitor of all except CypD6 . How do I discuss this please.

I can't for the life of me memorize p450 inducers and inhibitors! The sickfaces etc mnemonic doesnt work for me. Is there any video like sketchy for memorizing these enzymes? (Something free)

There are numerous substrates for CYP3A4 which could be a hazard if their metabolism is impaired too much: https://en.wikipedia.org/wiki/CYP3A4#Function

It's odd that we don't hear about too many people having problems arising from this. Has the inhibitory ability of CBD been overstated?

Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol

An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies - see table 1 for some numbers and extrapolations as regard CYP P450 isoforms.

My doctors never tried anything beyond codiene and tramadol. Codiene did absolutely nothing and tramadol I was popping like pez 16 a day with little effect. A 50mg tramadol did less than a single 500mg panadol.

After being my doctors for anything and going through the whole gabapentin, anti depressant for nerve pain etc, nothing worked.

So I was forced to do my own research, found out about the cytochrome p450 and the CYP2D6 enzyme and seemed to fit my symptoms so I got a test done. Doctors being shit he didn't understand the results and wouldn't give them to me so I didn't even know the results for over a year (turns out I'm normal except apparently clenazepan won't work properly, it works from my own experience)

Because of this I turned to my friends with connections and got a variety of opiates medications, oxycodone, DHC, morphine IR and ER. From my limited testing I found that oxy is about 1/3 as strong as morphine yet is supposed to be slightly stronger due to better absorption, DHC seemed to do something but only ever found 1 pill to try. Morphine works, instant release I didn't like as it peaked quickly causing a mild high and then fades out within 2 hours of taking it. Extended release actually works. 20-30mg seems enough that combined with cannabis I can get through a day without having to take enough to make me high. Any more and I start getting cloudy.

My doctors flat out refuse to give me anything stronger (was crying and begging in the doctors office for something else before I even knew what would work) they just offered me tramadol whilst saying I was taking too much. I was prescribed 16 a day with a max of 8 a day... I just couldn't get through a work day with any less and they kept giving them to me. Ended up with ED and temp regulation issues from the years I was on that dose.

So what do I do? I'm feeling more and more that becoming a heroin junkie might actually be a step up in life and that's terrifying.

Taken from the article (https://www.atlasobscura.com/articles/grapefruit-history-and-drug-interactions)

>Grapefruit has a high volume of compounds called furanocoumarins, which are designed to protect the fruit from fungal infections. When you ingest grapefruit, those furanocoumarins permanently take your cytochrome P450 enzymes offline. There’s no coming back. Grapefruit is powerful, and those cytochromes are donezo. So the body, when it encounters grapefruit, basically sighs, throws up its hands, and starts producing entirely new sets of cytochrome P450s. This can take over 12 hours.

>This rather suddenly takes away one of the body’s main defense mechanisms. If you have a drug with 10 percent bioavailability, for example, the drugmakers, assuming you have intact cytochrome P450s, will prescribe you 10 times the amount of the drug you actually need, because so little will actually make it to your bloodstream. But in the presence of grapefruit, without those cytochrome P450s, you’re not getting 10 percent of that drug. You’re getting 100 percent. You’re overdosing.

>And it does not take an excessive amount of grapefruit juice to have this effect: Less than a single cup can be enough, and the effect doesn’t seem to change as long as you hit that minimum.

I did have a really "heavy" trip once, when I pulverized some shrooms and mixed them with lemon juice (lemon tek, isn't it?). I suppose due to these being closely related, grapefruit would yield similar or more powerful trip. Mine was very introspective and changed me for the better (3 years smoke free, out of bad marriage - to name few benefits).

Has anyone tried it with grapefruit juice?

I researched that CBD will temporarily deactivate cytochrome P450 enzymes, thereby altering how we metabolize a wide range of compounds. If one is to take CBD and MDMA (100mg) together, at the same time orally- and the CBD is about 200mg which is quite a bit, does this increase any negative risk factors for the MDMA metabolizing into a compound that's undesirable?

Here is an excerpt from the research:

"The way CBD interacts with cytochrome P450 is pivotal; in essence, they deactivate each other. Preclinical research shows that CBD is metabolized by cytochrome P450 enzymes while functioning as a “competitive inhibitor” of the same liver enzymes. By occupying the site of enzymatic activity, CBD displaces its chemical competitors and prevents cytochrome P450 from metabolizing other compounds.

The extent to which cannabidiol behaves as a competitive inhibitor of cytochrome P450 depends on how tightly CBD binds to the active site of the metabolic enzyme before and after oxidation. This can change greatly, depending on how—and how much—CBD is administered, the unique attributes of the individual taking this medication, and whether isolated CBD or a whole plant remedy is used.

If the dosage of cannabidiol is low enough, it will have no noticeable effect on CYP activity, but CBD may still exert other effects. There is no clearly established cut-off dose, below which CBD does not interact with other drugs. A 2013 report on a clinical trial using GW Pharmaceutical’s Sativex, a whole plant CBD-rich sublingual spray, found no interactions with CYP enzymes when approximately 40mg of CBD were administered. A subsequent clinical trial, however, found that 25mg of orally administered CBDsignificantly blocked the metabolism of an anti-epileptic drug."

Summary:

I have a feeling all is well, considering the amount of MDMA taken with SSRI's, alcohol, and other drugs- but safety is top priority in this research and I wish to see if anyone has an answer on this.

Thanks in advance!!

I ran into a question where it basically asks which drug can inhibit cytochrome CYP3A4 to cause the build up of statins. I choice Metronidazole and got the question wrong (the correct answer was Clarithromycin).

I'm a little confused because I can't tell if the explanation of the question is trying to state only drugs that specifically inhibit cytochrome CYP3A4 cause the build up of statins, or if it's trying to state Metronidazole isn't a cytochrome P450 inhibitor. I tried researching into the inhibitor effects of Metronidazole and couldn't find a clear cut explanation.

Should we be assuming that only drugs that specifically inhibit cytochrome CYP3A4 are able to cause a build up of statins?

My grandma has been in a considerable amount of pain lately, so we've been thinking about trying CBD pills and balms for her. She's dealing with arthritis, mostly in the hands and neck.

She takes various medications that supposedly may be interfered with by CBD, including a statin (atorvastatin), a steroid (prednisolone), and a calcium channel blocker (diltiazem). Research seems to be scarce but indicates CBD may compete with these drugs for metabolization by Cytochrome P450 enzymes.

However, I've also read that you can safely take CBD with these other drugs by just taking them ~4 hours apart.

Her doctor is quite old-school and doesn't really know anything about CBD, so she couldn't offer us any advice on combining CBD with her other medications.

Would really appreciate some advice if you are knowledgeable or have experience. Thank you.

Since this seems to show up pretty frequently in Uworld pharma questions. Felt like high yield stuff.

We would not be living without our livers. Our livers detoxify our body from anything that could potentially harm us and actually has its own cleansing system called the cytochrome p450 enzymes system. There are drugs that may interact with CBD.

Why is this something to bring up about in relation to CBD? As most of us are coming to understand, CBD has the potential to effectively treat various illnesses and diseases by manipulating the endocannabinoid system with no “dirty” side effects. However, there may be one side effects to keep in mind, which is the inhibition of the cytochrome p450 enzyme system.

By inhibiting the cytochrome p450 system, it may lead to an overall increase in the processing of the other drugs in your system. Thus the other drugs may not metabolize as they should. This can lead to higher levels of the other medication in your system at one time, which can cause unwanted side effects and even overdose so, if you’re taking a medication that could be affected by cannabidiol, you may need a dose adjustment in order to take both medications safely.

https://www.cbd.how/cytochrome-p450-cbd-drug-interactions/

Hi, does anyone know if Silymarin inhibits or not the P450 / cyps enzymes? It would be silly if I would take this thinking I'm helping my liver but in the same time I would take other supplements, and if the P450 would be inhibited then those supplements wouldn't be metabolized properly.

Hopefully you got my idea, I might be wrong. Thanks in advance!

Microbial sulfur‐containing secondary metabolites show various biological activities and the C‐S bond‐forming in their biosynthetic metabolism has not been thoroughly understood. Here, we present genetic, biochemical and structural characterization of a cytochrome P450 monooxygenase CxnD exhibiting C‐S bond forming activity in S‐heterocyclization of chuangxinmycin biosynthesis. In vivo and in vitro analyses demonstrated that CxnD generated an indole‐fused dihydrothiopyran skeleton from a L‐Trp‐derived thiol intermediate. Furthermore, X‐ray crystal structure of CxnD in complex with a substrate analogue and structure‐based mutagenesis revealed intimate details of the substrate binding mode. A radical mechanism initiated by abstraction of the imino hydrogen atom or an electron from indole group of the substrate was proposed for CxnD, which provided valuable insights into the molecular basis for the intra‐molecular C(sp2)‐H thiolation by the P450 in chuangxinmycin biosynthesis.

https://ift.tt/2QPtCo0

I take Strattera 25mg, Wellbutrin 150mg & Brintellix 10mg daily.
(I suffer from dysthymic & anxiety disorder, OCPD, ADD and severe misophonia)

My doctor prescribes me this combination of drugs, but it seems a strange combination to me, considering many cytochrome 450 interactions.

Anyway, I recently changed the intake of vortioxetine from morning to just before bedtime. So before: I took all three pills together in the morning / After: Bupropion and Atomoxetine in the morning, Vortioxetine in the evening.

The mood changes that followed the days after this change lead me to suspect that there is a substantial difference in the resulting plasma concentrations of vortioxetine and its metabolites, after having changed the timing of intake.

So these are my questions:

• Could this be possible?

• Is it therefore advisable not to take drugs with a large P450 interaction together, but better spread as far apart as possible throughout the day?

• Is it even possible to obtain stable plasma concentrations when there are so many P450 interactions between the different drugs?

• Are there any studies about this subject?

• Has anyone already used this combination with his patients? (with good results?)