Some Parkinson’s Medicines May Hurt Levodopa Effectiveness
The use of several Parkinson’s disease medications was significantly associated with the increased abundance of a bacterial enzyme that converts levodopa to dopamine in the gut, potentially reducing levodopa’s availability in the brain, a study found.
In Parkinson’s patients with rapidly progressing disease, the approved therapy Comtan (entacapone) enhanced enzyme abundance, suggesting this medicine may reduce the impact of levodopa.
These findings support further research on the effect of Parkinson’s medications on gut microbial changes, the researchers noted.
The Dutch study, “Gut bacterial tyrosine decarboxylase associates with clinical variables in a longitudinal cohort study of Parkinsons disease,” was published in the journal NPJ Parkinson’s Disease.
Parkinson’s is marked by the loss of dopaminergic neurons in the brain — nerve cells that communicate with other neurons by releasing the signaling molecule known as dopamine.
A lack of dopamine leads to characteristic motor symptoms. Still, patients can also experience nonmotor symptoms such as cognitive impairment, depression, sleep deficits, and more gastrointestinal tract (GI) problems.
Levodopa, a precursor of dopamine, is one of the primary therapies used to treat the symptoms of Parkinson’s disease. The medicine is taken up by dopaminergic neurons, which convert it into dopamine.
Studies suggest that some bacteria in the gut produce an enzyme called tyrosine decarboxylase (TDC), which can convert levodopa into dopamine. This reaction may restrict the availability of levodopa in the bloodstream and eventually the brain, reducing its efficacy.
Researchers based at the University of Groningen in the Netherlands wondered whether increased exposure to other medicines used to treat Parkinson’s affected the abundance of bacterial TDC, which may ultimately impact levodopa efficacy.
To find out, the team measured the abundance of the bacterial gene that encodes for TDC — tdc — in fecal samples collected from 67 Parkinson’s patients and 65 healthy control individuals over two years. Patients and controls were matched in sex, age, body mass index (body fat content), and the use of antibiotics within the previous month.
In patients, the duration of both motor and nonmotor symptoms at the start of the study (baseline) was about eight years. From baseline to follow-up, there was a significant increase in the average levodopa equivalent daily dose (LEDD) — the total contribution made by each Parkinson’s medication.
During the study, there was a significant worsening in Parkinson’s patients of intellectual function, mood, and the activities of daily living, but a significant improvement in motor function, which “may be explained by the significant LEDD increase over time,” the team wrote.
At baseline, tdc was highly prevalent in both Parkinson’s patients (98%) and controls (97%). Likewise, similar results were seen at follow-up (98% vs. 100%). At that time, people with Parkinson’s tended to have a higher abundance of tdc than controls.
However, the increase in tdc abundance over time was significantly higher in patients compared with controls, with a mean increase of 2.6 times.
“The results indicate that, over time, tdc-gene abundance increases more rapidly in [Parkinson’s disease] patients compared to [healthy control] subjects,” the researchers wrote.
“Here, we did not find a significant correlation between levodopa dosage and tdc-gene abundance,” they added. “This discrepancy could be explained by the relatively low proportion of high levodopa dosages in this study.”
Patients’ GI symptoms were more severe than controls at both baseline and follow-up. Over time, only Wexner constipation scores increased significantly, but not Rome III scores for constipation and defecation combined.
Although the LEDD increased over time, there was no significant increased use for any individual medicine in patients, “possibly due to changes in medication type,” investigators wrote. When assessing treatments shared by both groups, at baseline, patients used significantly more anticholinergic medications, which are prescribed to help with motor symptoms.
The team then examined how different Parkinson’s therapies affected tdc levels over time. Dose changes in Comtan, Requip (ropinrole), and Mirapex (pramipexole) were associated with increases in tdc abundance, while Azilect (rasagiline) contributed to a reduction in tdc quantity over time.
Total Wexner constipation scores were significantly associated with less tdc abundance. After correcting for Wexner scores, the difference in exposure to Parkinson’s therapies still contributed to the tdc abundance results except for Requip.
“The results indicate that prolonged exposure of these specific anti-[Parkinson’s disease] medications, excluding levodopa, contributed to tdc-gene abundance independent of the changes in GI symptoms measured by Wexner scores,” the scientists noted.
Because Parkinson’s patients change their therapeutic doses during disease progression, the team compared the impact of tdc abundance of those who were slow progressing versus rapid progressing. Exposure to levodopa and Comtan significantly increased, while Mirapex use significantly decreased in the rapid group compared to the slow-progressing group.
In the slow-progressing group, Requip now significantly contributed to higher tdc levels, but not Comtan. This significance was no longer found when correcting for Wexner scores.
In the rapid group, however, only Comtan use significantly contributed to the change in tdc abundance.
“In summary, these observations indicate that the change in exposure to specific anti-[Parkinson’s disease] medications, like [Comtan], can be a significant contributing factor to an increase in tdc-gene abundance in rapid progressing [Parkinson’s disease] patients,” the researchers explained. At the same time, “other anti-[Parkinson’s disease] medications contribute to tdc-gene abundance in slow progressing [Parkinson’s disease] patients.”
“The present study implies important associations between anti-[Parkinson’s disease] medication and gut bacterial tdc-gene abundance,” the authors wrote. “These associations point toward complex interactions between anti-[Parkinson’s disease] medication, GI symptoms, and gut bacterial tdc-gene abundance, which warrants further research.”