REVIEW ARTICLE OPEN Mechanisms of peripheral levodopa resistance in Parkinson’s disease Milan Beckers 1,2 ✉ , Bastiaan R. Bloem 1,2 and Marcel M. Verbeek 1,2,3 Parkinson’s disease (PD) is an increasingly common neurodegenerative condition. The disease has a significant negative impact on quality of life, but a personalized management approach can help reduce disability. Pharmacotherapy with levodopa remains the cornerstone of treatment, and a gratifying and sustained response to this treatment is a supportive criterion that argues in favor of an underlying diagnosis of PD. Yet, in daily practice, it is not uncommon to encounter patients who appear to have true PD, but who nevertheless seem to lose the responsiveness to levodopa (secondary non-responders). Some patients may even fail to respond altogether (primary non-responders). Here, we address how two mechanisms of “peripheral resistance” may underlie this failing response to levodopa in persons with PD. The first explanation relates to impaired bowel motility leading to secondary bacterial overgrowth, and more specifically, to the excessive bacterial production of the enzyme tyrosine decarboxylase (TDC). This enzyme may convert levodopa to dopamine in the gut, thereby hampering entry into the circulation and, subsequently, into the brain. The second explanation relates to the systemic induction of the enzyme aromatic L-amino acid decarboxylase (AADC), leading to premature conversion of levodopa into dopamine, again limiting the bioavailability within the brain. We discuss these two mechanisms and focus on the clinical implications, potential treatments and directions for future research. npj Parkinson’s Disease (2022)8:56 ; https://doi.org/10.1038/s41531-022-00321-y INTRODUCTION Parkinson’s disease (PD) is the second-most common neurode- generative condition. The prevalence of the disease is growing faster than what could be explained by aging of the population alone. Consequently, the global number of PD patients is expected to more than double in the next twenty years, and might exceed 17 million by the year 2040 1 . The clinical presentation encompasses both motor and non-motor symp- toms, leading to progressive disability and a marked reduction in quality of life. Fluctuations in the response to pharmacotherapy, which are common in persons with advanced disease, are a further source of quality of life reduction 2,3 . A multidisciplinary management approach tailored to the needs of each individual can help reduce disability. Drug treatment is one of the four main pillars of this integrated approach, alongside device-aided therapies, multidisciplinary care and patient empow- erment 4 . Pharmacotherapy with levodopa has remained the cornerstone of the overall treatment plan ever since its introduc- tion in 1961 5 and usually helps to improve activities of daily living as well as quality of life 6,7 . Indeed, a gratifying and sustained response to dopaminergic drugs is a supportive criterion that argues in favor of an underlying diagnosis of PD 8 . Yet, in daily practice, it is not uncommon to encounter patients who appear to have true PD, but who nevertheless do not respond adequately to levodopa. Some patients may fail to respond altogether, even when there is otherwise little doubt about the diagnosis of PD 9,10 . Many other persons with PD develop a progressive resistance to even adequately dosed levodopa treatment over time, despite having initially enjoyed a beneficial response. In tertiary referral centers such as ours, these persons can number as high as 20%, but this percentage may be inflated because patients with a poor response to levodopa have a greater likelihood of being referred to a tertiary center of expertise. Consequently, these percentages may well be lower in more general clinics, but we suspect that future research might show such a diminished response to be a considerable issue in the general PD population as well. In this viewpoint, we discuss two mechanisms of “peripheral resistance” that may underlie this failing response to levodopa in persons with PD. Identification of these patients with a peripherally blunted levodopa responsiveness may have important clinical implications, as it could avoid the typically prolonged and time- consuming process of gradual further levodopa dosage increases, and instead motivate a timely start of alternative, more effective treatment strategies (e.g., with dopamine receptor agonists). Other approaches can target the mechanism of peripheral resistance directly. Timely installment of such treatments could help to avoid unnecessary disability. PERIPHERAL LEVODOPA PHARMACOKINETICS Since a dopamine deficit in the striatum is the neurochemical hallmark of PD, pharmacological substitution of dopamine is an important treatment modality. However, dopamine itself does not cross the blood-brain barrier (BBB) because of its high polarity and a lack of active transport proteins 11 . Its precursor levodopa, in contrast, is transported across the BBB by a selective transporter (L-type amino acid transporter 1, LAT1) 11 . Levodopa (L-3,4- dihydroxyphenylalanine, L-DOPA) is an amino acid which is naturally present in the human body. A diagram of its metabolism is provided in Fig. 1. After oral ingestion and passage through the stomach, levodopa is absorbed by a saturable facilitated transport system for large neutral amino acids (LNAA) 12 , mostly in the duodenum and proximal jejunum 13 . In the intestinal mucosa, AADC converts 1 Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. 2 Radboudumc Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands. 3 Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. ✉ email: Milan.Beckers@Radboudumc.nl www.nature.com/npjparkd Published in partnership with the Parkinson’s Foundation 1234567890():,;