The next step in my research will be to help set up a "Proof of Concept" trial, hopefully with an international team of experts in pharmacology, pharmacokinetics, drug development and Parkinson's disease.
This means scientifically answering the following question (or something like it).
"Does inhibition of CYP3A4 enzyme improve the bioavailability of orally administered levodopa?"
This is a deliberately simple question, the answer to which will hopefully open the door to more fundamantal research on drug selection, safety, dosing and the kinetics of enzyme induction and inhibition etc.
The direct answer to this question can only be obtained by testing over several hours, the serum concentration of levodopa in healthy subjects given C/L with and without a CYP3A4 inhibitor. It will have to be carried out in a hospital environment and subject to all the usual safety controls and protocols for such a trial. Grapefruit juice will probably not be used, since a synthetic, proven and well-documented CYP3A4 inhibitor will be more acceptable to the medical profession. This also means that the the trial can be blinded.
There are many reasons why we should answer this question.
1) The on/off effect due to the short half-life of levodopa considerably impacts the quality of life of PD patients. Partially inhibiting CYP3A4 may help patients lead a bettter life with less "off times".
2) The on/off effect may have long-term implications for dyskinesia, posssibly causing damage to synapses that must adapt to repeated under/over dosing of dopamine. Smoothing the concentration curve could mitigate this effect.
3) CYP3A4 potency is not the same for everyone. There is a large genetic variation in how patients respond to induction of this enzyme by drugs. Proving that CYP3A4 is involved may explain why some patients respond poorly to levodopa, whereas others are oversensitive.
4) Proving that CYP3A4 inhibits levodopa, could lead the way to effective therapy using herbal-based levodopa in countries where prescription meds are too expensive for most people. Mucuna Pruriens + GJ works better than MP alone. It's even better with Green tea extract + GJ. There are also other herbal CYP3A4 inhibitors that can be used. Drug-Drug Interactions (DDIs) are less likely in these countries, since the prescription medications involved are rarely used by the population concerned.
5) Proving CYP3A4 metabolism can bring some understanding to the impact of diet on PD symptoms, for example by taking into account the likely effects of polyphenols in fruit and vegetables.
6) This trial is not intended to encourage PD patients to drink Grapefruit juice without medical advice. That carries too many risks for DDIs. It is also the overkill enzyme inhibitor since it knocks out several CYPs at the same time for 24 hours or more and not enough is known about dosing GJ. A future possibility might be to select a more moderate, reversible CYP3A4 inhibitor taken in a triple-action pill (levodopa + DDC inhibitor + CYP3A4 inhibitor) to increase the useful life of levodopa to say 4-5 hours, with minimal risk of DDIs.
This "Proof of Concept" is not a big job, but it requires professional input, pharmacological expertise, lab resources and funding that we don't yet have.
We would like to put together an international research team so that the results will have the highest degree of credibility and outreach. To do this will require convincing doctors and consultants that this idea is worth persuing for the benefit of their patients. These are the people who can persuade the specialist researchers and their managers to look at the idea and eventually commit time, resources and money to it.
If, as PD patients and carers, you are convinced that this idea is worth persuing, then contact your PD specialist, give him/her all the information and files (my contact details are there) and use your personal experience to convince him to talk to his wider research network about it.
The team is already starting to form. I am now working with a very experienced pharmacologist, drug designer and PD specialist from a major European PD hospital unit to set up this team. This is a good start, but we need more and we need the best.
Spread the word.
Albert
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