The Effect of Catechol-O-Methyl Transferase Inhibition by Entacapone on the Pharmacokinetics and Metabolism of Levodopa in Healthy Volunteers

Keränen, Tapani; Gordin, A.; Harjola, Veli‐Pekka; Karlsson, MariAnne; Korpela, K.; Pentikäinen, Pertti J.; Rita, H.; Seppälä, L; Wikberg, Tom

doi:10.1097/00002826-199304000-00007

Cited by 106 publications

(66 citation statements)

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“…There were no differences in the C max of levodopa between LCE and LC after the first morning dose. This agrees with earlier studies conducted in healthy subjects [2] and patients with PD [5], which have shown that a single administration of LC and entacapone does not increase the C max of levodopa. With different dosing regimens, similar kinds of results (regarding t 1/2 , C min , C max , and AUC of levodopa) have been reported with repeated dosing of entacapone administered together with standard release levodopa/carbidopa [4][5] or with controlled-release levodopa/carbidopa [18].…”

Section: Discussionsupporting

confidence: 93%

“…Entacapone is a selective, reversible, peripherally acting COMT-inhibitor [2]. The pharmacokinetic (PK) profiles of entacapone and levodopa are comparable and the time course of COMT inhibition by entacapone also follows the plasma-concentration-time curve (AUC) of entacapone [2].…”

Section: Introductionmentioning

confidence: 99%

“…The pharmacokinetic (PK) profiles of entacapone and levodopa are comparable and the time course of COMT inhibition by entacapone also follows the plasma-concentration-time curve (AUC) of entacapone [2]. Therefore, entacapone is always taken together with each dose of levodopa/DDCI.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Kuoppamäki

Korpela

Marttila

et al. 2009

Eur J Clin Pharmacol

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Objectives To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC). Methods Open-label, randomized, two-period, activecontrolled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson's disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included C min , C max , C max −C min , AUC, t 1/2 , and t max .Results In healthy volunteers and PD patients, mean trough levels (C min ), C max , and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to C min , C max , and AUC, differences between the treatments in variability of levodopa concentrations (C max −C min ) were less consistent. Conclusions The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson's disease using similar dosing regimens.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Kuoppamäki

Korpela

Marttila

et al. 2009

Eur J Clin Pharmacol

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“…The genes of several dopamine receptors, the human tryptophan hydroxylase gene and the COMT gene however did not show an effect on CSF-HVA (Goldman et al, 1992;Adamson et al, 1995;Jönsson et al, 1997), which in contrast to plasma HVA is unlikely to reflect cortical dopaminergic neural activity (Neff et al, 1967;Meek and Neff, 1973;Aizenstein and Korf, 1978). The only trial that studied the effect of entacapone on plasma HVA however showed no significant alteration (Keranen et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Plasma Homovanillic Acid: A Significant Association with Alcoholism is Independent of a Functional Polymorphism of the Human Catechol-O-Methyltransferase Gene

Köhnke¹,

Wiatr²,

Kolb³

et al. 2002

Neuropsychopharmacol

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The central dopamine system seems to influence addictive disorders. Plasma homovanillic acid (HVA) is an indicator of central dopaminergic activity. In this study the hypothesis that plasma HVA is associated with alcoholism or with delirium tremens (DT) during alcohol withdrawal was tested. A functional genetic polymorphism of the enzyme catechol-O-methyltransferase (COMT) that participates in converting dopamine into its final metabolite HVA was investigated for an association with alcoholism or DT during alcohol withdrawal. In addition, a relation between the functional polymorphism of COMT and plasma HVA concentrations was studied. Plasma HVA concentrations and COMT genotypes were determined in 142 German alcoholics and 101 German healthy controls. Alcoholic patients were examined after a minimum of 3 weeks after cessation of drinking. Mean plasma HVA concentrations were significantly lower in alcoholic patients compared to healthy controls. A group of alcoholics with a history of DT during alcohol withdrawal (n ¼ 62) did not differ significantly in plasma HVA concentrations from alcoholics with a history of only mild withdrawal symptoms (n ¼ 67). The functional polymorphism of the human COMT gene was neither significantly associated with the diagnosis of alcoholism or DT during alcohol withdrawal nor with plasma HVA concentrations.

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“…4) Therefore, blood level of 3-OMD is continually high and 3-OMD accumulates in PD patients receiving long term L-DOPA therapy. 5) COMT inhibitor, such as entacapone, increases the area under the L-DOPA plasma concentration-time curve 6) and thus prolongs its clinical effect. 7) 3-OMD inhibits distribution of L-DOPA into the brain, since 3-OMD competes with L-DOPA at the blood-brain barrier transporter system.…”

Section: 3)mentioning

confidence: 99%

Effects of 3-<i>O</i>-Methyldopa, <small>L</small>-3,4-Dihydroxyphenylalanine Metabolite, on Locomotor Activity and Dopamine Turnover in Rats

Onzawa

Kimura

Uzuhashi

et al. 2012

Biological & Pharmaceutical Bulletin

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It has been well known that 3-O-methyldopa (3-OMD) is a metabolite of L-3,4-dihydroxyphenylalanine (L-DOPA) formed by catechol O-methyltransferase (COMT), and 3-OMD blood level often reaches higher than physiological level in Parkinson's disease (PD) patients receiving long term L-DOPA therapy. However, the physiological role of 3-OMD has not been well understood. Therefore, in order to clarify the effects of 3-OMD on physiological function, we examined the behavioral alteration in rats based on locomotor activity, and measured dopamine (DA) and its metabolites levels in rats at the same time after 3-OMD subchronic administration. The study results showed that repeated administrations of 3-OMD increased its blood and the striatum tissue levels in those rats, and decreased locomotor activity in a dose dependent manner. Although 3-OMD subchronic administration showed no significant change in DA level in the striatum, DA metabolite levels, such as 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA) were significantly decreased. After 3-OMD washout period (7 d), locomotor activity and DA turnover in those rats returned to normal levels. Furthermore, locomotor activity and DA turnover decreased by 3-OMD administration were recovered to normal level by acute L-DOPA administration. These results suggested that 3-OMD affect to locomotor activity via DA neuron system. In conclusion, 3-OMD itself may have a disadvantage in PD patients receiving L-DOPA therapy.Key words 3-O-methyldopa; L-3,4-dihydroxyphenylalanine; locomotor activity; dopamine turnover; rat Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra region of the basal ganglia, which results in movement-related symptoms. Current treatment for PD includes dopamine replacement therapy in the form of L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor to dopamine (DA) in its synthesis pathway that has been the gold standard of care for decades. More recently, DA receptor agonists, such as pramipexole, pergolide, and ropinirole, have become more commonly prescribed for the treatment of PD. Approximately 50% of PD patients, when treated with L-DOPA for more than 5 years, experience motor fluctuations such as the "wearing-off" phenomenon or the "no-on" phenomenon. 1) L-DOPA is commonly administered with aromatic amino acid decarboxylase (AADC) inhibitor, such as carbidopa or benserazide. 3-O-methyldopa (3-OMD) is a major metabolite of L-DOPA. 3-OMD is formed by catechol O-methyltransferase (COMT) in many organs including blood, peripheral tissues and brain.2) 3-OMD easily accumulates in several tissues (liver, kidney, brain, blood) because 3-OMD has much longer half-life (approximately 15 h) than L-DOPA. 2,3)It is reported that L-DOPA upregulates the expression and activity of COMT. 4) Therefore, blood level of 3-OMD is continually high and 3-OMD accumulates in PD patients receiving long term L-DOPA therapy.5) COMT inhibitor, such as entacapone, increases the area under ...

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The Effect of Catechol-O-Methyl Transferase Inhibition by Entacapone on the Pharmacokinetics and Metabolism of Levodopa in Healthy Volunteers

Cited by 106 publications

References 0 publications

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Plasma Homovanillic Acid: A Significant Association with Alcoholism is Independent of a Functional Polymorphism of the Human Catechol-O-Methyltransferase Gene

Effects of 3-<i>O</i>-Methyldopa, <small>L</small>-3,4-Dihydroxyphenylalanine Metabolite, on Locomotor Activity and Dopamine Turnover in Rats

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