Peter A. LeWitt, MD: One of the challenges in improving the therapeutics of Parkinson disease has a lot to do with drug delivery. Levodopa is a drug that is well absorbed in the upper GI [gastrointestinal] tract—upper small intestine, that is—in the duodenum and jejunum with other amino acids. But it has to get there. As Parkinson disease progresses in the brain, it’s also progressing systemically at different locations, 1 of which is the stomach.
The increasing problem of delayed and incomplete release of levodopa from the stomach, where it’s not absorbed at all in the sites of amino acid uptake, defines the stage of Parkinson disease when irregularity and motor fluctuations are most obvious. There may be other problems there, too, such as overgrowth of bacteria in the upper parts of the small intestine. But the failure of regular housekeeping functions of the stomach that deliver the drug with a small amount of fluid into that territory constitutes 1 of the reasons for irregularity.
This has been well documented from pharmacokinetic studies, and it is estimated that as many as one-third to one-half of patients have abnormal gastric emptying functions. Of course, patients might also have diabetes mellitus or other gastric problems that interfere with uptake beyond what Parkinson disease is imposing on them. But this is a common problem for which we have to find a future cure for—synucleinopathies—because the same α-synuclein that’s damaging in the brain and causing motor function symptoms is hitting the stomach hard.
It’s a prevalent problem. It’s one that doesn’t have a rapid-access answer in terms of medications that get the stomach to empty. Cold beverages seem to slow things down, but warm beverages don’t seem to enhance the release of medication. About all we can offer our patients is to take their medication a half an hour before or an hour after meals so there is not simultaneous competition of the stomach’s function and digestion in trying to get pills sent downstream to the upper small intestine.
There may also be the problem of protein intake. It is a major problem for every patient, and in fact, I encourage patients to determine whether they are sensitive to dietary protein, which, of course, is digested into amino acids. A large protein or amino acid intake competes with a small intake of levodopa at 100 mg, 150 mg, and so on. What wins? It’s the dietary protein for uptake. There isn’t a specific uptake mechanism for levodopa apart from all the other amino acids.
The best thing one can do is find out if there is a competition going on. Now, how can this be carried out? A patient might have lunch for 3 days in a row with a lot of protein to see 1 end of the extreme, and then have lunch for a few days in a row in which amino acids are used minimally by low-protein intake: salad, fruit, something like that. Patient can then report back whether that made a difference or that the days with high protein led to shutting down or an incomplete effect of levodopa.
If they don’t have that effect—and I would say the majority of patients don’t—then I don’t think patients need to be counseled to stay away from protein or to restrict it to the end of the day, as is so prominently stated on the internet. But it is a real effect and can have an impact on those patients who are very sensitive to doses of levodopa being interfered with by their dietary intake of protein.