A rapid non invasive L-DOPA-¹³C breath test for optimally suppressing extracerebral AADC enzyme activity - toward individualizing carbidopa therapy in Parkinson’s disease

Abstract

Background: Peripheral carbidopa (CD) levels directly impact on central dopamine (DA) production in Parkinson disease (PD) through extracerebral inhibition of dopa decarboxylase (AADC) resulting in an increase in levodopa (LD) bioavailability.

Objective: Recent data suggests that higher CD doses than those presently used in PD treatment may result in improved clinical response. Optimizing CD doses in individual patients may, therefore, result in ideal individualized treatment.

Methods: A single center, randomized, double-blind study was carried out recruiting 5 Parkinson’s disease (PD) patients already on LD/CD and 1 treatment näve PD patient using stable isotope labeled LD-1-¹³C as a substrate for a noninvasive breath test to evaluate individual AADC enzyme activity. Each patient was studied five times, receiving 200 mg LD-¹³C at each visit along with one of five randomized CD doses (0, 25, 50, 100 and 200 mg). The metabolite ¹³CO₂ in breath was measured for evaluating AADC enzyme activity and plasma metabolite levels for LD-¹³C and homovanillic acid (HVA) were measured for 4 hours.

Results: HVA in plasma and ¹³CO₂ in breath are metabolic products of LD. We found a significant positive correlation of ¹³CO₂ DOB AUC0-240 with serum HVA AUC0-240 following the oral dose of LD-1-¹³C for all 5 doses of CD (r² = 0.9378). With increasing inhibition of AADC enzyme activity with CD, we observed an increase in the plasma concentration of LD.We found an inverse correlation of the 13CO2 DOB AUC with serum LD-¹³C AUC. Our studies indicate the optimal dose of CD for maximal suppression of AADC enzyme activity can be determined for each individual from ¹³CO₂ generation in breath.

Conclusions: The LD-breath test can be a useful noninvasive diagnostic tool for evaluation of AADC enzyme activity using the biomarker ¹³CO₂ in breath, a first step in personalizing CD doses for PD patients.

Figure 1

Biotransformation pathways for L-DOPA (LD)

Figure 2

a) Breath ¹³CO₂ levels represented as DOB values vs time after LD-¹³C dose with different CD doses. Patient 5; fixed 200 mg LD-¹³C dose. b) Plasma HVA levels vs time after LD-¹³C dose with different CD doses. Patient 5; fixed 200 mg LD-¹³C dose.

Figure 2

a) Breath ¹³CO₂ levels represented as DOB values vs time after LD-¹³C dose with different CD doses. Patient 5; fixed 200 mg LD-¹³C dose. b) Plasma HVA levels vs time after LD-¹³C dose with different CD doses. Patient 5; fixed 200 mg LD-¹³C dose.

Figure 3

a) Linear correlation of breath Average DOB AUC₂₄₀ vs Average plasma HVA AUC₂₄₀ ng/mL /h n = 6; R² = 0.983. b) Linear correlation of breath Average DOB AUC₂₄₀ vs Average plasma LD AUC₂₄₀ ng/mL /h n = 6; R² = 0.929.

Figure 3

a) Linear correlation of breath Average DOB AUC₂₄₀ vs Average plasma HVA AUC₂₄₀ ng/mL /h n = 6; R² = 0.983. b) Linear correlation of breath Average DOB AUC₂₄₀ vs Average plasma LD AUC₂₄₀ ng/mL /h n = 6; R² = 0.929.

Figure 4

Metabolic pathway of ¹³C-LD to generate ¹³CO₂ DA and HVA.