COMT inhibition with tolcapone does not affect carbidopa pharmacokinetics in parkinsonian patients in levodopa/carbidopa (Sinemet®)

Jorga, Karin; Nicholl, David

doi:10.1046/j.1365-2125.1999.00027.x

Cited by 3 publications

(1 citation statement)

References 10 publications

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“…The reason for this is unknown but interestingly tolcapone has been shown to dose-dependently increase the plasma concentrations of the AADC inhibitor benserazide (but not carbidopa [22]) when given to patients with Parkinson's disease [24]. Whether this interaction contributes to the increase reported for midday and evening peak levodopa concentrations during tolcapone and whether this is clinically relevant has not been established [3].…”

Section: ■ Simultaneous Inhibition Of Comt and Aadcmentioning

confidence: 99%

Drug-drug interactions with levodopa modulating treatment responses in Parkinson's disease

Haefeli

2007

J Neurol

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Section: ■ Simultaneous Inhibition Of Comt and Aadcmentioning

confidence: 99%

Drug-drug interactions with levodopa modulating treatment responses in Parkinson's disease

Haefeli

2007

J Neurol

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Clinical Pharmacokinetic and Pharmacodynamic Properties of Drugs Used in the Treatment of Parkinson??s Disease

Deleu

Northway

Hanssens

2002

Clinical Pharmacokinetics

287

189

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Current research in Parkinson's disease (PD) focuses on symptomatic therapy and neuroprotective interventions. Drugs that have been used for symptomatic therapy are levodopa, usually combined with a peripheral decarboxylase inhibitor, synthetic dopamine receptor agonists, centrally-acting antimuscarinic drugs, amantadine, monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors. Drugs for which there is at least some evidence for neuroprotective effect are certain dopamine agonists, amantadine and MAO-B inhibitors (selegiline). Levodopa remains the most effective drug for the treatment of PD. Several factors contribute to the complex clinical pharmacokinetics of levodopa: erratic absorption, short half-life, peripheral O-methylation and facilitated transport across the blood-brain barrier. In patients with response fluctuations to levodopa, the concentration-effect curve becomes steeper and shifts to the right compared with patients with stable response. Pharmacokinetic-pharmacodynamic modelling can affect decisions regarding therapeutic strategies. The dopamine agonists include ergot derivatives (bromocriptine, pergolide, lisuride and cabergoline), non-ergoline derivatives (pramipexole, ropinirole and piribedil) and apomorphine. Most dopamine agonists have their specific pharmacological profile. They are used in monotherapy and as an adjunct to levodopa in early and advanced PD. Few pharmacokinetic and pharmacodynamic data are available regarding centrally acting antimuscarinic drugs. They are characterised by rapid absorption after oral intake, large volume of distribution and low clearance relative to hepatic blood flow, with extensive metabolism. The mechanism of action of amantadine remains elusive. It is well absorbed and widely distributed. Since elimination is primarily by renal clearance, accumulation of the drug can occur in patients with renal dysfunction and dosage reduction must be envisaged. The COMT inhibitors entacapone and tolcapone dose-dependently inhibit the formation of the major metabolite of levodopa, 3-O-methyldopa, and improve the bioavailability and reduce the clearance of levodopa without significantly affecting its absorption. They are useful adjuncts to levodopa in patients with end-of-dose fluctuations. The MAO-B inhibitor selegiline may have a dual effect: reducing the catabolism of dopamine and limiting the formation of neurotoxic free radicals. The pharmacokinetics of selegiline are highly variable; it has low bioavailability and large volume of distribution. The oral clearance is many-fold higher than the hepatic blood flow and the drug is extensively metabolised into several metabolites, some of them being active. Despite the introduction of several new drugs to the antiparkinsonian armamentarium, no single best treatment exists for an individual patient with PD. Particularly in the advanced stage of the disease, treatment should be individually tailored.

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Tolcapone

Keating¹,

Lyseng‐Williamson²

2005

CNS Drugs

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Tolcapone (Tasmar) is a selective, reversible inhibitor of peripheral and central catechol-O-methyltransferase (COMT). Results of well designed studies indicate that oral tolcapone is an effective adjunct to levodopa plus a peripheral dopa-decarboxylase inhibitor (DDCI) in patients with fluctuating Parkinson's disease. Tolcapone significantly improves levodopa-induced motor fluctuations and significantly reduces levodopa requirements. The drug is generally well tolerated, with the most commonly occurring adverse events being dopaminergic related. Thus, tolcapone is a useful option in patients with fluctuating Parkinson's disease who are receiving levodopa/DDCI and are not responding to, or are not candidates for, other adjunctive treatments.

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COMT inhibition with tolcapone does not affect carbidopa pharmacokinetics in parkinsonian patients in levodopa/carbidopa (Sinemet®)

Cited by 3 publications

References 10 publications

Drug-drug interactions with levodopa modulating treatment responses in Parkinson's disease

Drug-drug interactions with levodopa modulating treatment responses in Parkinson's disease

Clinical Pharmacokinetic and Pharmacodynamic Properties of Drugs Used in the Treatment of Parkinson??s Disease

Tolcapone

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