Substantial renal conversion of L-threo-3,4-dihydroxyphenylserine (droxidopa) to norepinephrine in patients with neurogenic orthostatic hypotension.

BACKGROUND: The pressor effect of L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxidopa, Northera™) results from conversion of L-DOPS to norepinephrine (NE) in cells expressing L-aromatic-amino-acid decarboxylase (LAAAD). After L-DOPS administration the increase in systemic plasma NE is too small to explain the increase in blood pressure. Renal proximal tubular cells abundantly express LAAAD. Since NE generated locally in the kidneys could contribute to the pressor effect of L-DOPS, in this study we assessed renal conversion of L-DOPS to NE. METHODS: Ten patients who were taking L-DOPS for symptomatic orthostatic hypotension had blood and urine sampled about 2 h after the last L-DOPS dose. L-DOPS and NE were assayed by alumina extraction followed by liquid chromatography with electrochemical detection. Data were compared in patients off vs. on levodopa/carbidopa. RESULTS: In patients off levodopa/carbidopa the ratio of NE/L-DOPS in urine averaged 63 times that in plasma (p = 0.0009 by t test applied to log-transformed data). In marked contrast, in the three patients on levodopa/carbidopa the ratio of NE/L-DOPS in urine did not differ from that in plasma. CONCLUSION: There is extensive renal production of NE from L-DOPS. Carbidopa seems to attenuate the conversion of L-DOPS to NE in the kidneys. Further research is needed to assess whether the proposed paracrine effect of L-DOPS in the kidneys contributes to the systemic pressor response.

Determination of D,L-threo-3,4-dihydroxyphenylserine and of the D- and L-enantiomers in human plasma and urine.

DL-threo-3,4-Dihydroxyphenylserine (DOPS) is increasingly being investigated for treatment of disorders involving defects of the sympathetic nervous system, such as Parkinson's disease, Shy-Drager syndrome and congenital dopamine-beta-hydroxylase deficiency. Whilst L-DOPS is converted by aromatic L-amino acid decarboxylase into natural norepinephrine in vitro, D-DOPS inhibits this process. There are no data on the interaction between D- and L-DOPS in vivo because a reliable method for the measurement of the D- and L-enantiomers in plasma and urine is lacking. We describe here such a method based on reversed-phase chromatography after derivatization with o-phthaldialdehyde and N-acetyl-L-cysteine. Good separation was achieved with this procedure (resolution factor 2.33). Two simple and sensitive methods are also presented for total D,L-DOPS estimation, based on reversed-phase chromatography with electrochemical detection after either deproteinization (DP) or liquid-liquid extraction (LE) as sample preparation steps. The two methods gave identical results (regression line DOPS (DP) = 1.026 DOPS (LE) + 33.28; r = 0.997; n = 52). Excellent agreement was found between the sum of the D- and L-DOPS concentrations and the measured total D,L-DOPS concentration (regression line DOPS (D + L) = 0.955 DOPS (total, LE) + 116.65; r = 0.992; n = 100).