Pharmacokinetics of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, in man

Heikkinen, Helena; Saraheimo, Markku; Antila, Saila; Ottoila, Pekka; Pentikäinen, Pertti J.

doi:10.1007/s002280000244

Cited by 33 publications

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“…After oral administration, significantly higher plasma levels and a higher AUC value were attained with tolcapone than with entacapone, a reflection not only of the better bioavailability but also the slower elimination of tolcapone. These results are in parallel with human studies (Kerä nen et al, 1994;Jorga et al, 1998;Heikkinen et al, 2001).…”

Section: Discussionsupporting

confidence: 84%

“…In healthy volunteers the elimination half-life (t 1/2␤ ) of tolcapone (1.3 h) is clearly longer than that of entacapone (0.4 h), and the total clearance of tolcapone (7.1 l/h) is much smaller than that of entacapone (51.9 l/h) (Jorga et al, 1998;Heikkinen et al, 2001). At therapeutic oral doses, both drugs are rapidly eliminated with an apparent t 1/2 of 1.6 to 3.4 h, but tolcapone generally has a longer duration of action as assessed by inhibition of COMT activity in erythrocytes (Kerä nen et al, 1994;Dingemanse et al, 1995).…”

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confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Entacapone and Tolcapone after Acute and Repeated Administration: A Comparative Study in the Rat

Forsberg

Lehtonen²,

Heikkinen³

et al. 2003

J Pharmacol Exp Ther

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Two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were compared in the rat to elucidate the actual differences between their pharmacokinetics and pharmacodynamics after single and repeated administration. Their inhibitory potencies were also compared in vitro. After intravenous administration (3 mg/kg), the elimination half-life (t 1/2␤ ) of entacapone (0.8 h) was clearly shorter than that of tolcapone (2.9 h). The striatum/serum ratio of tolcapone was 3-fold higher than that of entacapone. After a single oral dose (10 mg/kg), both entacapone and tolcapone produced an equal maximal degree of COMT inhibition in peripheral tissues, but tolcapone inhibited striatal COMT more effectively than did entacapone. After the 7-day treatment (10 mg/kg twice daily), COMT activity had recovered to a level of 67 to 101% of control within 8 h after the last dose of entacapone. In tolcapone-treated animals, there was still extensive COMT inhibition present in peripheral tissues, and the degree of inhibition was higher than that attained after a single dose. The pharmacokinetic-pharmacodynamic modeling revealed that a plateau of COMT inhibition near the maximal attainable inhibition was reached already by plasma concentrations below 2000 ng/ml, both with entacapone and tolcapone. Entacapone and tolcapone inhibited equally rat liver COMT in vitro with K i values of 10.7 and 10.0 nM, respectively. In conclusion, tolcapone has a longer duration of action and a better brain penetration than entacapone. The results also suggest that peripheral COMT is inhibited continuously when tolcapone is dosed at 12-h intervals, but this was not seen with entacapone.The second-generation catechol-O-methyltransferase (COMT, EC 2.1.1.6) inhibitors, entacapone and tolcapone, are indicated as adjuncts to standard levodopa-dopa decarboxylase inhibitor therapy in Parkinson's disease. They increase the bioavailability of levodopa by inhibiting its peripheral metabolism to an inactive metabolite, 3-O-methyldopa. COMT inhibitors improve the efficacy of the levodopa-dopa decarboxylase inhibitor therapy by prolonging the duration of action and the clinical benefit of levodopa (Mä nnistö and Kaakkola, 1999;Kaakkola, 2000).Entacapone and tolcapone apparently behave differently both in experimental animals and humans. However, as a rule, entacapone and tolcapone have been studied only individually; their pharmacokinetics and pharmacodynamics have not been compared thoroughly after single and repeated dosing. Actually, very little is known about their pharmacodynamics in different tissues after repeated dosing. Furthermore, only the relationship between the plasma drug concentration and COMT activity in erythrocytes has been studied previously (Dingemanse et al., 1995(Dingemanse et al., , 1996Forsberg et al., 2002).A few available studies on entacapone and tolcapone in rats suggest that entacapone is eliminated faster than tolcapone and its oral bioavailability is lower than that of tolcapone. After intravenous administration ...

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Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Entacapone and Tolcapone after Acute and Repeated Administration: A Comparative Study in the Rat

Forsberg

Lehtonen²,

Heikkinen³

et al. 2003

J Pharmacol Exp Ther

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“…Though COMT inhibitors have significantly improved the treatment of advanced PD patients there are still many problems with the present inhibitors. The elimination half-life for (Heikkinen et al, 2001). The major problems of present COMT inhibitors may be divided in four main categories which are partially linked with each other: (1) pharmacoki netic problems, (2) pharmacodynamic problems, (3) efficacy problems, and (4) safety problems.…”

Section: Introductionmentioning

confidence: 99%

Problems with the Present Inhibitors and a Relevance of New and Improved COMT Inhibitors in Parkinson’s Disease

Kaakkola¹

2010

International Review of Neurobiology

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“…7 The pharmacokinetic properties of levodopa and entacapone are quite similar, with half-lives of about 1 to 2 hours. 8,9 Therefore, entacapone is administered concomitantly with each dose of a levodopa/DDC inhibitor.…”

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confidence: 99%

Entacapone Increases Levodopa Exposure and Reduces Plasma Levodopa Variability When Used With Sinemet CR

Paija¹,

Laine²,

Kultalahti³

et al. 2005

Clinical Neuropharmacology

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Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.

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Pharmacokinetics of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, in man

Cited by 33 publications

References 0 publications

Pharmacokinetics and Pharmacodynamics of Entacapone and Tolcapone after Acute and Repeated Administration: A Comparative Study in the Rat

Pharmacokinetics and Pharmacodynamics of Entacapone and Tolcapone after Acute and Repeated Administration: A Comparative Study in the Rat

Problems with the Present Inhibitors and a Relevance of New and Improved COMT Inhibitors in Parkinson’s Disease

Entacapone Increases Levodopa Exposure and Reduces Plasma Levodopa Variability When Used With Sinemet CR

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