Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine prodrug L-DOPS

Abstract

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.

Figure 1

Steps in the metabolism of L-threo-3,4-dihydroxyphenylserine (L-DOPS). After cellular uptake via the neutral amino acid transporter (NAAT), L-DOPS may be converted by DOPS aldolase to glycine and protocatechualdehyde, by catechol-O-methyltransferase (COMT) to form O-methyl-DOPS (O-Me-DOPS), or by L-aromatic-aminoacid-decarboxylase (LAAAAD) to form norepinephrine (NE). NE is metabolized by monoamine oxidase (MAO) to dihydroxyphenylglycolaldehyde (DOPEGAL). DOPEGAL is converted to dihydroxyphenylglycol (DHPG) by aldose/aldehyde reductase (AR) or to dihydroxymandelic acid (DHMA) by aldehyde dehydrogenase (ALDH). Because DHPG and DHMA are both catechols, they are subject to O-methylation catalyzed by COMT, forming methoxyhydroxyphenylglycol (MHPG) or vanillylmandelic acid (VMA). Carbidopa (CAR) inhibits LAAAD, and entacapone (ENT) inhibits COMT.

Figure 2

Plasma mean (± SEM) concentrations of (top) L-threo-3,4-dihydroxyphenylserine (L-DOPS) and (bottom) norepinephrine (NE) as functions of time after oral administration of L-DOPS (400 mg) with 200 mg of placebo (PLA, open circles), 200 mg of carbidopa (CAR, black circles), or 200 mg of entacapone (ENT, black squares).

Figure 3

Mean (± SEM) changes in systolic blood pressure from baseline as functions of time after oral administration of L-threo-3,4-dihydroxyphenylserine (L-DOPS) (400 mg) with 200 mg of placebo (PLA, open circles), 200 mg of carbidopa (CAR, black circles), or 200 mg of entacapone (ENT, black squares).

Figure 4

Plasma mean (± SEM) concentrations of (top) dihydroxyphenylglycol (DHPG) and (bottom) dihydroxymandelic acid (DHMA) as functions of time after oral administration of L-threo-3,4-dihydroxyphenylserine (L-DOPS) (400 mg) with 200 mg of placebo (PLA, open circles), 200 mg of carbidopa (CAR, black circles), or 200 mg of entacapone (ENT, black squares).

Figure 5

Mean (± SEM) changes in systolic blood pressure from baseline as functions of (left) changes in plasma norepinephrine (NE) from baseline and (right) changes in plasma dihydroxyphenylglycol (DHPG) from baseline after oral administration of L-threo-3,4-dihydroxyphenylserine (L-DOPS) (400 mg) with 200 mg of placebo (PLA, open circles), 200 mg of carbidopa (CAR, black circles), or 200 mg of entacapone (ENT, black squares). In the left panel, lines of best fit for ENT have long dashes, for PLA short dashes, and for CAR are solid.