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Contamination of the Norepinephrine Pro‐Drug Droxidopa by Dihydroxyphenylacetaldehyde
Author(s) -
Holmes Courtney S,
Goldstein David S
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.773.11
Subject(s) - chemistry , orthostatic vital signs , ingestion , norepinephrine , chromatography , medicine , dopamine , biochemistry , blood pressure
Background Droxidopa (3,4‐threo‐L‐dihydroxyphenylserine, L‐DOPS) is a norepinephrine (NE) pro‐drug under development to treat orthostatic hypotension. 3,4‐Dihydroxyphenylacetaldehyde (DOPAL) is a toxic catecholaldehyde. Methods Thirteen subjects took 400 mg Droxidopa orally, with blood sampled at baseline and 1, 2, 3, 6, 24, and 48 hours after drug administration and assayed for plasma L‐DOPS, NE, and DOPAL. Droxidopa in acidic solution was vacuum centrifuged for 1 hour at 30 degrees centigrade. Results Droxidopa contained 0.01% DOPAL. At 6 hours, all subjects had DOPAL detected in plasma (1.89 nmol/L, p=0.0001). Across the sampling times plasma DOPAL correlated with plasma L‐DOPS (r=1.00). The mean increment in plasma DOPAL averaged more than 4 times the mean increment in plasma NE (0.39 nmol/L). In 2 patients with Parkinson disease and orthostatic hypotension, DOPAL was detected at baseline (0.12 nmol/L) and increased by about 70‐fold after Droxidopa. After 1 hour of vacuum centrifugation, L‐DOPS was converted completely to DOPAL. Interpretation Droxidopa is contaminated with DOPAL. After Droxidopa ingestion DOPAL is detectable in plasma. Droxidopa is converted completely to DOPAL under conditions resembling those in the stomach.