The role of Cytochrome P450 enzyme inhibi... - Cure Parkinson's

Cure Parkinson's

25,342 members26,642 posts

The role of Cytochrome P450 enzyme inhibitors in herbal treatments of Parkinson's Disease

wriga profile image
33 Replies

At least 6 Cytochrome P450 enzymes (CYP 450) degrade or metabolize L-Dopa, Azilect and Ropinirole, reducing their bioavalability and lifetime in the brain. They are highly present in the gut, the liver and some even in the brain. Conventional medications largely ignore their presence and action. Herbal remedies such as grapefruit, green tea extract and others contain very effective CYP 450 inhibitors which could increase the efficacy and lifetime of Parkinson drugs, but their use is often discouraged because they can also modify the efficacy of 75% of drugs used to treat other conditions, sometimes leading to overdosing. I have made a survey of some PD drugs degraded by CYP 450 enzymes and the corresponding herbal remedies that may influence their bioavailability.

You can find the file here :

researchgate.net/publicatio...

Written by
wriga profile image
wriga
To view profiles and participate in discussions please or .
Read more about...
33 Replies
Juliegrace profile image
Juliegrace

Very interesting, thank you.

M1tz1 profile image
M1tz1

Hi Wriga,

I seem to recall that one has to be careful consuming grapefruit in combination with cholesterol medication and other pharmaceutical drugs. 🙂

wriga profile image
wriga in reply to M1tz1

Hi M1tz1,

You should be careful with most statins, blood pressure meds, heart meds, etc, the list is long, since the CYP enzymes reduce their bioavailability (not the efficacy). This is all known and the same applies to most PD meds. That's why they dont stay long in the blood (Not usually more than one passage via the liver, about 90 minutes) Grapefruit juice and green tea extend that by inhibiting many CYP enzymes. But rather than banning GJ, I make the case of using that knowledge with all the proper precautions to extend the lifetime of these very short lived PD meds. My short experience is that it works.

But you must take all the precautions with other meds. Your doctor will probably tell you to avoid it.

Gioc profile image
Gioc in reply to wriga

Thanks Wriga, this is something I've been looking for for some time to combine with thiamine and niacin. Something that stabilized the levodopa by preventing the highest peak in the blood and then go to zero after more or less an hour and a half. I'll try.

wriga profile image
wriga in reply to Gioc

Hi Gio,

Before you start read the article well and if possible all the références (there are more than 150 pages, esp the first ref by Ramon Cacabelos on CYP coding of PD meds and print out table 1 of this ref for guidance. If you have questions pls ask.

Gioc profile image
Gioc in reply to wriga

I'll do it until I fully understand the subject before I try. thank you very much!

Gio

MBAnderson profile image
MBAnderson in reply to wriga

If you're using grapefruit juice to extend the life of a drug, isn't that comparable to increasing the dose of that drug, and if so, how do you know how much of a dose you are ending up with?

In other words, grapefruit juice will cause some drugs to accumulate beyond their intended blood sermon level, won't it? Are you concerned about some drugs accumulating to a toxic level?

wriga profile image
wriga in reply to MBAnderson

Hi MBA,

That's exactly right. Inhibiting CYP enzymes means that serum levels of drugs dont decline as fast, so with the same intake the peak dose will be higher and later, and could become toxic. To avoid this risk, initial doses should be lower. How much lower ? That will depend on your genetic CYP polymorphism : slow, intermediate or fast CYP metabolisers. We all start off at different levels of CYP activity. CYP inhibition levels the field. PD drugs have an added difficulty in that serum drug levels dont equate to drug levels in the brain. There is bound to be a delay to cross the BBB. During this delay, CYP activity in the liver will be actively metabolising the drug. Hense the short therapeutic life of the drugs. There needs to be a lot of research done to understand this, but just avoiding CYP enzyme inhibitors is not the answer.

MBAnderson profile image
MBAnderson in reply to wriga

wriga,

Thank you for your reply.

The question is, if you’re drinking grapefruit juice to extend the half-life of your PD pharmaceuticals, Mucuna P or anything for that matter, how do you know by how much you’ve extended it? Probably, most PWP are taking a half-dozen pharmaceuticals each of which would be affected differently, i.e., 2 drugs are extended by 10%, 2 by 20%, and 2 by 30%, but What if I don’t want those last 2 drugs extended at all and I can’t stop taking them.

To avoid the risk of their pharmaceuticals accumulating to a toxic level, you advise them to lower the initial dose, but, as you point out, they can't know by how much unless they also know if they are of slow, intermediate, or fast metabolisers, which IMHO not a single person on this forum knows.

The likelihood of us reducing The dose by exactly the right amount so that the efficacy is not diminished, but is extended is pretty close to 0. Also, Isn't there A fair chance Of ending up with more levodopa than was intended?

I appreciate your link and the information you provided, but I feel trying to tinker with the bioavailability, efficacy, and half-life of pharmaceuticals by drinking grapefruit juice is shooting in the dark.

Thank you.

Marc

wriga profile image
wriga in reply to MBAnderson

Hello Marc,

Thanks for your well considered input. I fully endorse your question and sadly I don't have an answer to it. I don't think anyone has. I would however suggest that knowing of the existence of CYP enzymes and their impact on meds but ignoring these impacts is just as worrying or even irresponsable. Shooting in the dark seems to be the standard for PD meds. I still have a valid prescription for a PD med that lets me choose the dosage over a factor of 4 depending on how I feel it's working ! This from an experienced Dr that I respect. Now knowing that one med can impact on another I stopped all meds for 3 days before starting GJ or Green Tea Extract and then tested each one individually and then in pairs to try to find the best dosages and combinations. This is my experience in exact science kicking in even tho biomedecine is much less predictable than physics. It has taken a long time to find what works for me and the job is not finished. I know that for others the results would not be the same. Just for guidance, the impact on bioavailability of CYP enzyme inhibition for PD meds (and others) is not at all marginal ie. not 20 or 30% but very much higher. It can double or triple ! That's why overdosing can be a real problem, but also why the subject is important for meds with low bioavailability,

Hope this helps.

Albert

MBAnderson profile image
MBAnderson in reply to wriga

Albert,

This information you provided is really important. Thank you for that.

People will have learned from your post that they can end up with considerably more levodopa or any of their other pharmaceuticals than they intended. Unfortunately, it adds another layer of complexity to what is already mind-boggling.

Marc

wriga profile image
wriga in reply to MBAnderson

Just corrected a few autocorrection errors. If you see any French words, that's why. Yes Marc, mind boggling, in comparison, physics is easy.

wriga profile image
wriga in reply to MBAnderson

It can also work the other way. For some prodrugs like codein, the precursor does not get converted into the useful drug, so it simply doesn't work.

Gioc profile image
Gioc in reply to wriga

Bravo Albert, thank you for this very useful information.

A question for you: the difficulty that you found and to regulate the ldopa or more on all the other medicines?

If a person took only ldopa like me for now I should not have much difficulty to regulate it, don't you think?

wriga profile image
wriga in reply to Gioc

Hi Gio,

Getting a sustained flow of l-dopa to the brain is key. I doubt that we need very much, maybe only a few mg per day, but without peaks and lows. The first problem is the DDC enzyme. Carbidopa deals with that. If you're talking Mucuna P, this is only partially resolved with Green Tea, but it does help. After that comes the CYP enzymes. They severely limit the half-life of L-dopa. Their inhibition makes a big difference and I believe (no real proof yet) that the combination of Green Tea Extract and GJ works best. Dont overdo either. GJ is persistent and takes days to be eliminated. One avantage I found was GJ stopped nausea when talking Mucuna P. There must be an explanation for this.

Gioc profile image
Gioc in reply to wriga

I see ,

I use madopar, so the GJ should be good enough for now.

Well! the absence of nausea is a good indicator.

is a wonderful discovery. (if it finds application)

Thank you Albert.

dangilio profile image
dangilio

I read that even the cbd oil interacts with Cytochrome P450, my mom is taking oil cbd for a few months with a noticeable improvement. also takes 1/2 tablet of modapar, it could be that for now the half tablet was enough thanks to the interaction of the cbd?

wriga profile image
wriga in reply to dangilio

Hi dangilio. Yes, but I think grapefruit juice is a more powerful CYP inhibitor. Cbd may have other properties that are useful tho. Madapar contains benserazide that is a peripherally-acting DOPA decarboxylase inhibitor, like carbidopa. In this case green tea extract may be unnecessary for the DDC inhibition and grapefruit juice the best option. Always carefully check on other meds first.

dangilio profile image
dangilio in reply to wriga

thx for the reply wriga.... what do you suggest to do? continue with cbd?

dangilio profile image
dangilio in reply to dangilio

wriga.. should i stop with cbd?

wriga profile image
wriga in reply to dangilio

Hi Dangilio,

I'm not compétent to give advice or an opinion on particular cases. I limit my interventions as far as possible to compiling facts and observations to try to build up a coherent story or model that peolpe can use to make their own opinions. I haven't put cd oil into this story yet, so I can't answer your question. Sorry.

dangilio profile image
dangilio in reply to wriga

ok thanks wriga

wriga profile image
wriga

Cbd oil strongly inhibits CYP 3A4 and 3A5 as does grapefruit juice. But Cbd is also metabolised by other CYP enzymes. GJ is therefore likely to increase the potency of Cbd. Also dont use GJ with codein for the same reason.

ncbi.nlm.nih.gov/pmc/articl...

ncbi.nlm.nih.gov/m/pubmed/2...

wriga profile image
wriga

I should have included the following ref on CYP interactions with many drugs.

Its an excellent overview.

ncbi.nlm.nih.gov/m/pubmed/2...

Despe profile image
Despe

Wriga, thanks for your excellent research!

My husband is on MP standardized extract 20% L-dopa X 2/day. He drinks green tea with his morning dose and takes Vitamin C. Would the efficacy of MP be even more extended with the addition of GJ? He is not on any conventional drugs except a compounded T4/T3 thyroid med.

Are you still on HDT?

wriga profile image
wriga in reply to Despe

Hi Despe,

I do believe that GJ will help MP last longer. The problem remains that Green Tea is less effective in preventing perpheral decarboxylation than carbidopa, and GJ does not help this. Also thyroid drugs have a narrow therapeutic window. GJ could lead To overdose. What are the molecule(s) he's talking ?

Despe profile image
Despe in reply to wriga

Hi Wriga,

GJ could lead to overdose of what, thyroid meds?

He is taking T4 (45MCG) T3 (5MCG). The doctor and the FM pharmacist increased it to 50MCG and 7.5MCG as a result of the recent test he had, but hasn't started the increased dose yet. He's got a very few left of the old dose to finish before he starts the new one. Actually, we would like to try porcine thyroid hormones, but we will see. . .

Thank you.

wriga profile image
wriga in reply to Despe

Hi Despe,

I'm absolument not competent to give advice on specific cases, so I can't answer your question. Take a look at my reply to MDAnderson's more general question to see my views. Its a very complex subject.

Despe profile image
Despe in reply to wriga

Thanks, Albert! Indeed, it's a very complex subject for non-scientific people like me. :)

Gioc profile image
Gioc

Hello Wriga, grapefruit juice looks promising for me, even if it's too early to say, yesterday low of madopar without major problems.

wriga profile image
wriga in reply to Gioc

Hi Gio,

0.75cl GJ per day ? = 7.5ml, I'm surprised at how little you are taking, Are you sure of your units ? I'm on a full glass = 200 ml. Anyway, pleased it's helping. I would not advise to cut down much on the madapar because you still need the DDC inhibitor to stop peripheral decarboxylation. GJ does not help that.

Albert

wriga profile image
wriga

Hi Gio,

I strongly believe that 0.75L of GJ per day is too much. Above 0.5L per day, there may be inhibition of CYP enzymes in the liver and that could have a serious effect on the lifetimes of other drugs that people may take. There is a long list of common drugs that can go into overdose when taken with GJ. Futhermore the effects can depend on how much GJ you drink and be dangerously long lasting when the liver is affected.

You must always check with your doctor and read the notice of any drugs you take before drinking GJ.

For more reading see : D.G. Bailey et al.

Grapefruit–medication interactions: Forbidden fruit or avoidable consequences?

ncbi.nlm.nih.gov/pmc/articl...

Gioc profile image
Gioc in reply to wriga

ok Albert, I only take madopar and CJ daily was just a test of a couple of days to see if there was any substantial change in the cycles of the ldopa and there is!

I think I will follow your advice and I will settle on 0.250 L of CJ day for one or two weeks. It will not hurt me, but if I use other medicines I would be very cautious with CJ. Thank you very much .

Gio

You may also like...

Parkinson's Disease: emerging treatment target, the NLRP inflammasome.

Hyperstimulated immune cells in the brain are emerging as a hallmark feature of most...

Honey for parkinson disease

contains a considerable percentage of L-DOPA, a commonly employed drug against Parkinson’s [213]....

New and current hope for Parkinson's Disease

Tass glove, or the CUE1 ,the Probiotic PS128,(gut/brain) Fecal transplant, Focused Ultrasound The...

Trehalose as a promising therapeutic candidate for the treatment of Parkinson's disease - 2019

mechanisms and therapeutic impacts...

Parkinson disease risks: correctly identifying environmental factors for a chronic disease

disease (PD) is now the world’s fastest growing brain disease; however, the factors underlying this...