Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS
Identifieur interne : 000327 ( Main/Exploration ); précédent : 000326; suivant : 000328Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS
Auteurs : David S. Goldstein ; Courtney Holmes ; Latoya Sewell ; Sandra Pechnik ; Irwin J. KopinSource :
- The Journal of Clinical Pharmacology [ 0091-2700 ] ; 2011-01.
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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 1/15000th 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.
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DOI: 10.1177/0091270010363476
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS</title><author><name sortKey="Goldstein, David S" sort="Goldstein, David S" uniqKey="Goldstein D" first="David S." last="Goldstein">David S. Goldstein</name></author><author><name sortKey="Holmes, Courtney" sort="Holmes, Courtney" uniqKey="Holmes C" first="Courtney" last="Holmes">Courtney Holmes</name></author><author><name sortKey="Sewell, Latoya" sort="Sewell, Latoya" uniqKey="Sewell L" first="Latoya" last="Sewell">Latoya Sewell</name></author><author><name sortKey="Pechnik, Sandra" sort="Pechnik, Sandra" uniqKey="Pechnik S" first="Sandra" last="Pechnik">Sandra Pechnik</name></author><author><name sortKey="Kopin, Irwin J" sort="Kopin, Irwin J" uniqKey="Kopin I" first="Irwin J." last="Kopin">Irwin J. 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Goldstein</name><affiliation><wicri:noCountry code="subField">Bethesda Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Holmes, Courtney" sort="Holmes, Courtney" uniqKey="Holmes C" first="Courtney" last="Holmes">Courtney Holmes</name><affiliation><wicri:noCountry code="subField">Bethesda Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Sewell, Latoya" sort="Sewell, Latoya" uniqKey="Sewell L" first="Latoya" last="Sewell">Latoya Sewell</name><affiliation><wicri:noCountry code="subField">Bethesda Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Pechnik, Sandra" sort="Pechnik, Sandra" uniqKey="Pechnik S" first="Sandra" last="Pechnik">Sandra Pechnik</name><affiliation><wicri:noCountry code="subField">Bethesda Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Kopin, Irwin J" sort="Kopin, Irwin J" uniqKey="Kopin I" first="Irwin J." last="Kopin">Irwin J. Kopin</name><affiliation><wicri:noCountry code="subField">Bethesda Maryland</wicri:noCountry></affiliation></author></analytic><monogr></monogr><series><title level="j">The Journal of Clinical Pharmacology</title><idno type="ISSN">0091-2700</idno><idno type="eISSN">1552-4604</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2011-01">2011-01</date><biblScope unit="volume">51</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="66">66</biblScope><biblScope unit="page" to="74">74</biblScope></imprint><idno type="ISSN">0091-2700</idno></series><idno type="istex">0A9FFCB715E27F7295686042811237E6BB80A174</idno><idno type="DOI">10.1177/0091270010363476</idno><idno type="ArticleID">JCPH2227</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0091-2700</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>DHPG</term><term>DOPS</term><term>Dihydroxyphenylserine</term><term>Parkinson's disease</term><term>autonomic failure</term><term>dihydroxymandelic acid</term><term>dihydroxyphenylglycol</term><term>norepinephrine</term><term>orthostatic hypotension</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Goldstein, David S" sort="Goldstein, David S" uniqKey="Goldstein D" first="David S." last="Goldstein">David S. Goldstein</name><name sortKey="Holmes, Courtney" sort="Holmes, Courtney" uniqKey="Holmes C" first="Courtney" last="Holmes">Courtney Holmes</name><name sortKey="Kopin, Irwin J" sort="Kopin, Irwin J" uniqKey="Kopin I" first="Irwin J." last="Kopin">Irwin J. Kopin</name><name sortKey="Pechnik, Sandra" sort="Pechnik, Sandra" uniqKey="Pechnik S" first="Sandra" last="Pechnik">Sandra Pechnik</name><name sortKey="Sewell, Latoya" sort="Sewell, Latoya" uniqKey="Sewell L" first="Latoya" last="Sewell">Latoya Sewell</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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