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Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS
Author(s) -
Goldstein David S.,
Holmes Courtney,
Sewell LaToya,
Pechnik Sandra,
Kopin Irwin J.
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010363476
Subject(s) - entacapone , carbidopa , norepinephrine , endocrinology , orthostatic vital signs , catechol o methyl transferase , medicine , chemistry , prodrug , blood pressure , pharmacology , parkinson's disease , levodopa , dopamine , biochemistry , allele , disease , gene
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 1/15000th 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.