Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications

Abstract

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder primarily affecting dopaminergic neuronal systems, with impaired motor function as a consequence. The most effective treatment for PD remains the administration of oral levodopa (LD). Long-term LD treatment is frequently associated with motor fluctuations and dyskinesias, which exert a serious impact on a patient’s quality of life. The aim of our study was to determine the pharmacokinetics of LD: used as monotherapy or in combination with ropinirole, in patients with advanced PD. Furthermore, an effect of ropinirole on the pharmacokinetics of 3-OMD (a major LD metabolite) was assessed. We also investigated the correlation between the pharmacokinetic parameters of LD and 3-OMD and the occurrence of motor complications. Twenty-seven patients with idiopathic PD participated in the study. Thirteen patients received both LD and ropinirole, and fourteen administered LD monotherapy. Among 27 patients, twelve experienced fluctuations and/or dyskinesias, whereas fifteen were free of motor complications. Inter- and intra-individual variation in the LD and 3-OMD concentrations were observed. There were no significant differences in the LD and 3-OMD concentrations between the patients treated with a combined therapy of LD and ropinirole, and LD monotherapy. There were no significant differences in the LD concentrations in patients with and without motor complications; however, plasma 3-OMD levels were significantly higher in patients with motor complications. A linear one-compartment pharmacokinetic model with the first-order absorption was adopted for LD and 3-OMD. Only mean exit (residence) time for 3-OMD was significantly shorter in patients treated with ropinirole. Lag time, V/F, CL/F and tmax of LD had significantly lower values in patients with motor complications. On the other hand, AUC were significantly higher in these patients, both for LD and 3-OMD. 3-OMD Cmax was significantly higher in patients with motor complications as well. Our results showed that ropinirole does not influence LD or 3-OMD concentrations. Higher 3-OMD levels play a role in inducing motor complications during long-term levodopa therapy.

Efficacy and safety of non‐ergot dopamine‐receptor agonists as an adjunct to levodopa in advanced Parkinson's disease: A network meta‐analysis

“…Wang et al [ 17 ] proposed that ropinirole stimulates D2‐MSNs, inducing an imbalance between D1‐ and D2‐MSN‐based motor pathways, which may lead to ropinirole inducing more dyskinesia per unit of normal movement. Adamiak‐Giera et al [ 18 ] indicated that ropinirole may cause dyskinesia by influencing 3‐O‐methyldopa (3‐OMD) concentration. 3‐OMD is a major metabolite of levodopa.…”

Clinical benefit of MAO-B and COMT inhibition in Parkinson’s disease: practical considerations

“…COMT is expressed in all peripheral tissues and in the central nervous system (CNS) while the peripheral component is critical for the CNS bioavailability of levodopa. Peripheral COMT not only reduces levodopa concentrations, but its product 3-OMD also competes with levodopa in terms of blood–brain barrier transport and CNS dopamine uptake, and thus worsens motor function (Wade and Katzman 1975 ; Nyholm 2006 ; Adamiak et al 2010 ; Adamiak-Giera et al 2021 ). For this reason, COMT inhibition acts not only by increasing levels of levodopa transported into the CNS, but also through a sustained reduction of its competitor 3-OMD, an effect that is potentiated upon presence of dopamine decarboxylase inhibitors (DDCI) (Bonifacio et al 2012 ).…”

Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson’s Disease: Observations and Dilemmas after 10 Years of Real-Life Experience

“…Improving the adverse pharmacokinetics of levodopa is a constant challenge [15][16][17], with several alternatives widely used. Further positive effects are expected from the introduction of the new peripheral catechol-O-methyltransferase inhibitor (COMT-i) opicapone [18] and the reversible monoamine oxidase B inhibitor (MAO-Bi) and glutamate modulator safinamide [19,20].…”