Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure
- David S. GoldsteinAffiliated withClinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke National Institutes of HealthNINDS, NIH, 10 Center Drive MSC-1620 Building 10 Room 6N252 Email author
- , Courtney HolmesAffiliated withClinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke National Institutes of Health
- , Horacio KaufmannAffiliated withMount Sinai School of Medicine
- , Roy FreemanAffiliated withBeth Israel Deaconess Medical Center
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Oral L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic catechol amino acid, increases standing blood pressure and improves standing ability in patients with neurogenic orthostatic hypotension, by conversion of L-DOPS to norepinephrine (NE) outside the brain. This study assessed the pharmacokinetics of L-DOPS, NE, and dihydroxyphenylglycol (DHPG), the main neuronal metabolite of NE, in patients with primary chronic autonomic failure from pure autonomic failure (PAF) or multiple system atrophy (MSA).
In 5 MSA and 4 PAF patients, antecubital venous blood was drawn during supine rest and plasma levels of catechols measured at various times for 48 hours after a single oral dose of 400 mg of L-DOPS.
Plasma L-DOPS peaked at 1.9 µg/ml (9 µmol/L) about 3 hours after drug administration, followed by a monoexponential decline with a half-time of 2–3 hours in both patient groups. Plasma NE and DHPG also peaked at about 3 hours, but at much lower concentrations (4 and 42 nmol/L). Compared to the MSA group, the PAF group had a smaller calculated volume of distribution of L-DOPS and up to 10-fold lower plasma NE levels at all time points. Plasma NE was above baseline in MSA even at 48 hours after L-DOPS.
The relatively long half-time for disappearance of L-DOPS compared to that of NE explains their very different attained plasma concentrations. The similar NE and DHPG responses in PAF and MSA suggests production of NE from LDOPS mainly in non-neuronal cells. Persistent elevation of plasma NE in MSA suggests residual release of NE from sympathetic nerves.
Key wordsDOPS norepinephrine dihydroxyphenylglycol autonomic failure sympathetic nervous system
- Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure
Clinical Autonomic Research
Volume 14, Issue 6 , pp 363-368
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- autonomic failure
- sympathetic nervous system
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- Author Affiliations
- 1. Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke National Institutes of Health, Bethesda (MD), USA
- 2. NINDS, NIH, 10 Center Drive MSC-1620 Building 10 Room 6N252, Bethesda (MD), 20892-1620, USA
- 3. Mount Sinai School of Medicine, New York (NY), USA
- 4. Beth Israel Deaconess Medical Center, Boston (MA), USA