Premium
Entacapone improves the availability of l ‐dopa in plasma by decreasing its peripheral metabolism independent of l ‐dopa/carbidopa dose
Author(s) -
Heikkinen Helena,
Varhe Anu,
Laine Tarmo,
Puttonen Jaakko,
Kela Marjo,
Kaakkola Seppo,
Reinikainen Kari
Publication year - 2002
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2002.01654.x
Subject(s) - entacapone , carbidopa , pharmacokinetics , crossover study , placebo , pharmacology , catechol o methyl transferase , medicine , chemistry , levodopa , parkinson's disease , biochemistry , alternative medicine , disease , pathology , gene , allele
AimsEntacapone is a peripherally acting catechol‐O‐methyltransferase (COMT) inhibitor. To improve the benefits of oral l ‐dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of l ‐dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of l ‐dopa given as standard release l ‐dopa/carbidopa.MethodsSix different doses of l ‐dopa/carbidopa were investigated in this placebo‐controlled, double‐blind (regarding entacapone), randomized, single‐dose study in 46 young healthy males. The subjects were divided into three groups ( n = 14–16). Two different l ‐dopa/carbidopa doses were administered to each subject (50/12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four‐way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of l ‐dopa, its metabolites, carbidopa, and entacapone were determined.ResultsEntacapone increased the AUC(0,12 h) of l ‐dopa to a similar extent at all doses of l ‐dopa/carbidopa, that is by about 30–40% compared with placebo ( P < 0.001, 95% CI 0.15, 0.40). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean C max values for l ‐dopa at all l ‐dopa/carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of l ‐dopa were maintained for a longer period at all doses of l ‐dopa/carbidopa. Entacapone also decreased the peripheral formation of 3‐O‐methyldopa (3‐OMD) to about 55–60% of the placebo treatment level ( P < 0.001, 95% CI −0.72, −0.35) and increased the mean AUC(0,12 h) of 3,4‐dihydroxy‐phenylacetic acid (DOPAC) 2–2.6‐fold compared with placebo ( P < 0.001, 95% CI 0.60, 1.10). The mean AUC(0,12 h) of 3‐methoxy‐4‐hydroxy‐phenylacetic acid (HVA) following entacapone was approximately 65–75% of that observed with placebo ( P < 0.001–0.05, 95% CI –0.76, −0.01) at each l ‐dopa/carbidopa dose except the 50/12.5 mg dose ( P > 0.05, 95% CI –0.59, 0.05). The metabolic ratios (MR, AUC metabolite/AUC l ‐dopa) also confirmed that entacapone significantly decreased the proportion of 3‐OMD ( P < 0.001, 95% CI −0.85, −0.68) and HVA ( P < 0.001, 95% CI −1.01, −0.18) in plasma at each l ‐dopa/carbidopa dose, whereas the AUC DOPAC/AUC l ‐dopa ratio was increased again at all doses ( P < 0.001, 95% CI 0.26, 0.90). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did l ‐dopa/carbidopa affect the pharmacokinetics of entacapone.ConclusionsThe 200 mg dose of entacapone similarly and significantly increases the AUC of l ‐dopa by changing the metabolic balance of l ‐dopa independent of the l ‐dopa/carbidopa dose and therefore entacapone is likely to have a similar l ‐dopa potentiating effect independent of l ‐dopa dose.