This is a simplified version of my research into how L-Dopa is metabolised in humans and my current understanding of how its duration in the blood may be very significantly improved simply by drinking a glass of Grapefruit juice per day.
Earlier this month, I posted a detailed scientific article on the metabolism of L-Dopa and the possibility that Cytochrome P450 enzymes could be impacting the bio-availability of L-Dopa in the blood. The post generated quite a few replies and comments, but many of you said that you had difficulty in understanding the document. I agree that the subject is extremely complicated, with its own particular jargon, but due to the controversial nature of my conclusions, to be credible it also had to be detailed.
First, some background about who I am and how I came upon this idea. I am an experienced research scientist (chemistry/physics), now retired from a leading international research centre. I have published many scientific articles during my career but, importantly, never in this field. One year ago, when I was first diagnosed with Parkinson’s disease, I knew absolutely nothing about this subject. I put a lot of effort into learning about Parkinson’s disease, and after a few months I began to understand some aspects of the pharmacology and pharmacokinetics of drugs used to treat it.
In a subject as intensively documented as this, there are very few obvious gaps in the knowledge available to researchers. There are however, as in all scientific fields, areas where the accepted wisdom fails to stand up to detailed scrutiny. This is particularly true in a field which is not an exact science such as this. Being new to this field, I initially thought that I must have misunderstood something. However the more I looked into it, the more I became convinced that some aspects of the established wisdom did not add up. I felt the need to do more detailed research to try to find out what might be wrong. Since I am no longer employed by a recognised institution and have no experience or realistic credibility in this field, it was not my intention to publish articles on this subject. However, in the light of what I may have stumbled on, I feel it is important to share this with people with Parkinson’s disease.
Trying to prove an alternative to the established wisdom is a very big challenge. But in this case, if it turns out to be true, it could be very helpful for people with Parkinson’s disease. For a scientist who believes there really is a problem to be solved, it becomes an obsession. Paradoxically, being new to the subject is a great advantage for a research scientist. He is not boxed in by past experience of research that wasted time and effort and didn’t end well. So there are no areas he can’t go into. “You can think outside the box, because you don’t have one”. That’s why young scientists are often more creative than more experienced ones.
Good and bad enzyme inhibitors
My intuition led me to look into research on enzyme inhibitors and to focus on the most important system in drug metabolism, Cytochrome P450 enzymes. If the overlooked process in the metabolism of L-Dopa was indeed a CYP enzyme, I realised that I would have strayed outside the box. CYP enzymes are the killing fields for drug developers because they are the most important source of drug-drug interactions and a major issue for drug safety. But I was to discover an even more controversial issue. The only practical route to improve the bio-availability of Levodopa in the face of CYP enzymes would be to explore whether the source of the biggest safety issues in drug-food interactions, Grapefruit, could be transformed into a very positive benefit for people with Parkinson’s disease. This is a very uncomfortable place to be.
A summary of the research
It is recognised that Levodopa is strongly metabolised by two main enzymes, DDC and COMT. There are drugs available to inhibit these enzymes and are regularly prescribed. Even so, its bio-availability and half-life in the blood remains poor. I suspected that there might be a third enzyme that kicked in when the other two were blocked. If this were true, it would not take much effort for a specialised laboratory to identify it and propose a solution. So why was there no published research on this and no drug available to deal with it?
When I looked at the likely candidates for a hypothetical third enzyme, one clearly stood out and with it the reasons why big pharma will not touch it. It’s called CYP3A4 (sorry for the jargon). CYP3A4 is the most potent drug-degrading enzyme in the intestines and the liver. CYP enzymes are also the cause of drug-drug interactions that have very serious implications for drug safety. Any drug that unintentionally inhibits CYP enzymes, even though it may have been designed for something else, comes with a long list of safety warnings on drug-drug interactions that seriously limit its use. For drug-drug interactions to occur, you must take two drugs within a short time scale time, often for completely different conditions. One drug is “boosted” (I prefer to say “protected”) by the action of the other drug on the CYP enzyme.
Warnings relating to Drug-Drug Interactions
A significant number of drugs carry warnings against taking two apparently quite unrelated drugs simultaneously. These warnings relate to serious drug-drug interactions. Patients are not normally given any explanation for this, they are just told not to mix them!
In the vast majority of these cases, the link between the two drugs (let’s call them Drug A and Drug B), is in their opposing reaction to a very common enzyme, a protein called CYP3A4 whose role is to protect organs from toxins getting into the blood. Both of the drugs are chemically attracted to the same enzyme, usually in the intestine or the liver, so that the enzyme can degrade them into smaller non-toxic products, but as you will see, with two very different outcomes.
Drug A follows the normal process. It binds to the enzyme, is degraded by it and is finally released in a degraded state. The enzyme remains active and available to degrade other molecules of the same drug. As a result, less of the active drug gets into the bloodstream and that which does is progressively cleared from the blood by the liver. The drug dose is calculated to take this process into account and is much higher than if it were not degraded by the enzyme.
Drug B also binds to the enzyme and is partially degraded by it, but then the process takes a very different path. One component of the degraded Drug B is a chemically active species, and instead of being released, it reacts chemically with the enzyme and permanently deactivates it. The enzyme is said to be irreversibly inhibited. A new supply of enzyme protein must then be regenerated by the cells that express it and this can take many hours or days. During this post-inhibition period, if drug A is ingested, it will no longer be degraded to the same degree by the enzyme and very much more of it can get into the bloodstream where it will remain for a longer period. Consequently when Drug A is co-ingested with Drug B, the former is overdosed and this can have serious consequences.
The most serious interactions of this type occur when Drug A is rapidly metabolised by an enzyme and therefore has a very low bio-availability and when Drug B strongly inhibits the same enzyme. The pharmaceutical industry takes this very seriously and tries to avoid making drugs that can be involved in accidental drug-drug interactions by this process. In some cases however, two drugs are deliberately prescribed together so that by inhibiting a given enzyme, Drug B protects and improves the bio-availability of Drug A. In the treatment of Parkinson’s disease, the DDC enzyme inhibitor Carbidopa, is co-administered with Levodopa, and a COMT enzyme inhibitor is also available to improve the bio-availability of Levodopa.
What has this to do with Parkinson’s disease?
Even when the two important enzymes, DDC and COMT are inhibited, Levodopa still has a very low bio-availability and is rapidly eliminated from the bloodstream. This unexplained observation raises the question of whether a third enzyme takes up the task of degrading Levodopa and becomes dominant when the other two are inhibited. This opens up a clear research opportunity to identify the enzyme concerned and to find a solution to improve the low bio-availability of Levodopa for Parkinson’s disease patients.
The most potent enzymes that degrade more than 70% of all drugs are the Cytochrome P450 type. CYP3A4 is most active in the gut (70%) and the liver (30%). Here the % relates to the fraction of total CYP enzymes in each organ, bearing in mind that the liver has 100 times more CYP3A4 than the gut.
There is no direct experimental proof, but significant and credible indirect evidence, that CYP3A4 degrades Levodopa. This uncertainty concerning the interaction between Levodopa and CYP3A4 still needs to be clarified experimentally.
Why has this not been researched before? It surely has been investigated by the pharmaceutical industry, but not pursued because of the high risk of drug-drug interactions that would likely make this line of research unprofitable. It is therefore unlikely that a commercial CYP3A4 inhibitor would ever be developed to inhibit CYP3A4.
Are there any natural inhibitors?
The answer to this question can be found in numerous drug safety warnings. Grapefruit juice is the most extensively researched food product known to cause drug-drug (or in this case drug-food) interactions mediated by CYP3A4. Many drugs that carry a safety warning to avoid drug-drug interactions also warn against the consumption of Grapefruit juice prior to, or simultaneously with the use of the drug. These grapefruit-juice induced drug interactions are very well documented. Grapefruit juice contains a very potent natural CYP3A4 inhibitor and therefore should be given the same consideration as any other drug.
One glass (250ml) of grapefruit juice is proven to totally and irreversibly inhibit CYP3A4 in the intestine. When consumed on a daily basis, the amount of CYP3A4 in the liver is also reduced. When CYP3A4 is inhibited by Grapefruit juice, more than 24 hours (up to 3 days) are needed before the enzyme activity is totally renewed, so a daily dose causes a cumulative effect in the liver. This extends the time a drug remains active in circulation in the blood.
So where does this leave Parkinson’s Patients?
I am fairly certain that Levodopa is metabolised by CYP3A4 and becomes the dominant metabolic pathway when DDC and COMT enzymes are inhibited. However, I could be wrong so this still needs to be proven experimentally. It could be a significant cause of the low bio-availability and short half-life of Levodopa in the blood.
The potency of grapefruit juice as an inhibitor of CYP3A4 is proven. If the above hypothesis is correct, grapefruit juice could be used to increase the bio-availability and extend the half-life of Levodopa in the blood, especially if taken in conjunction with DDC and COMT inhibitors. Because of the proven safety issues associated with Grapefruit juice in relation to many other drugs, this could turn out to be a very contentious issue indeed. In its favour, grapefruit has no safety issues for people in good health are not medicated. In fact it’s good for you.
In the meantime, I am carrying out my own personal trial with the support of my GP and getting good results. He even suggested that the subject would make a good subject for a research thesis in pharmacology.
If you are taking other drugs for unrelated conditions, you should first discuss the matter with your Doctor before drinking grapefruit juice on a regular basis and consult in detail the reference by D.G. Bailey on grapefruit-induced drug-drug interactions.
Ref. : D.G. Bailey et al.
Grapefruit–medication interactions: Forbidden fruit or avoidable consequences?
CMAJ. 2013 Mar 5; 185(4): 309–316.
The full scientific paper lays out in detail the evidence for this summary. If you would like to read it, you can find it here: researchgate.net/publicatio...