Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine prodrug L-DOPS.
BACKGROUND
L-threo-3,4-dihydroxyphenylserine (L-DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti-parkinsonian drugs might interact with L-DOPS. We tested whether L-aromatic amino-acid decarboxylase inhibition by carbidopa (CAR) attenuates L-DOPS conversion to NE and blocks the pressor effect of L-DOPS, whereas catechol-O-methyltransferase inhibition by entacapone (ENT) interferes with L-DOPS metabolism and augments the pressor effect.


METHODS
Twelve patients with autonomic failure took 400 mg of L-DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L-DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured.


RESULTS
L-DOPS+PLA and L-DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L-DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15,000 th that in L-DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L-DOPS.


CONCLUSIONS
After L-DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L-DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O-methylation and evokes vasoconstriction before reaching the systemic circulation.
Goldstein
David S
DS
Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1620, USA. goldsteind@ninds.nih.gov
Holmes
Courtney
C
Sewell
LaToya
L
Pechnik
Sandra
S
Kopin
Irwin J
IJ
D000368:Aged; D000978:Antiparkinson Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002230:Carbidopa / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology*; D004311:Double-Blind Method; D015103:Droxidopa / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000188:drug therapy; D009570:Nitriles / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy; D011355:Prodrugs; D054970:Pure Autonomic Failure / Q000188:drug therapy; D014661:Vasoconstriction / Q000187:drug effects
D000978:Antiparkinson Agents; D002396:Catechols; D009570:Nitriles; D011355:Prodrugs; C071192:entacapone; D015103:Droxidopa; D002230:Carbidopa; D009638:Norepinephrine