Contamination of the norepinephrine prodrug droxidopa by dihydroxyphenylacetaldehyde.
BACKGROUND
L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxidopa) is a norepinephrine (NE) prodrug under development to treat orthostatic hypotension. 3,4-Dihydroxyphenylacetaldehyde (DOPAL), an endogenous catecholaldehyde produced by enzymatic oxidative deamination of dopamine, is toxic to catecholaminergic neurons. Based on the observation of increasing plasma DOPAL after oral administration of L-DOPS to a patient, we examined whether other subjects also had DOPAL in their plasma after droxidopa administration, and whether droxidopa is contaminated with DOPAL.


METHODS
Thirteen subjects took 400 mg droxidopa orally. We sampled venous blood at baseline and 1, 2, 3, 6, 24, and 48 h after drug administration and assayed L-DOPS, NE, and DOPAL by use of liquid chromatography with electrochemical detection (LC-ED). Droxidopa in acidic solution (20:80 mixture of 0.04 mol/L phosphoric acid:0.20 mol/L acetic acid) was vacuum centrifuged for 1 h at 30 degrees C and then assayed by LC-ED.


RESULTS
Droxidopa contained 0.01% DOPAL. At 6 h after droxidopa, all subjects had detectable DOPAL in plasma (1.89 nmol/L, P = 0.0001). Across the sampling times, plasma DOPAL correlated with plasma L-DOPS (r = 0.996). The mean increment in plasma DOPAL was more than 4 times that in plasma NE (0.39 nmol/L). In 2 patients with Parkinson disease and orthostatic hypotension, DOPAL was detected in plasma at baseline (0.12 nmol/L) and increased by about 70-fold after droxidopa. Vacuum concentration of droxidopa in the acid solution converted L-DOPS to DOPAL completely.


CONCLUSIONS
Droxidopa is contaminated with DOPAL. After oral droxidopa administration, DOPAL is detected in plasma of humans. Droxidopa is susceptible to extensive nonenzymatic conversion to DOPAL.
Holmes
Courtney
C
Clinical Neurocardiology Section, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1620, USA.
Whittaker
Noel
N
Heredia-Moya
Jorge
J
Goldstein
David S
DS
D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000097:blood; D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000097:blood*; D002853:Chromatography, Liquid; D015103:Droxidopa / Q000097:blood*; D004340:Drug Contamination; D005260:Female; D006801:Humans; D007024:Hypotension, Orthostatic / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy
D000978:Antiparkinson Agents; D015102:3,4-Dihydroxyphenylacetic Acid; C007430:3,4-dihydroxyphenylacetaldehyde; D015103:Droxidopa