Effect of Entacapone, a COMP Inhibitor, on the Pharmacokinetics and Metabolism of Levodopa After Administration of Controlled-Release Levodopa-Carbidopa in Volunteers

Ahtila, S.; Kaakkola, Seppo; Gordin, A.; Korpela, K.; Heinävaara, Sirpa; Karlsson, MariAnne; Wikberg, Tom; Tuomainen, Päivi; Männistö, Pekka T.

doi:10.1097/00002826-199502000-00006

Cited by 53 publications

(28 citation statements)

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“…It also seemed as if levodopa was accumulated extracellularly in brain and this could indicate a longer T½ of levodopa in brain compared to peripheral blood. Both the DDI benserazide and the COMT-inhibitor entacapone were given during the period of oral medication and adding a DDI or entacapone to levodopa have previously been shown to increase the T½ of levodopa in blood (35,(58)(59)(60)(61)(62). Adding the COMT-inhibitor entacapone to levodopa/DDI also results in higher levels of levodopa in brain (66).…”

Section: Discussionmentioning

confidence: 99%

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Nord¹

2017

Linköping University Medical Dissertations

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindrin...

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Section: Discussionmentioning

confidence: 99%

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Nord¹

2017

Linköping University Medical Dissertations

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“…Carbidopa t max was highly variable (range 0.5-4 h). This was independent carbidopa C max and AUC values, particularly after high entacapone doses [12]. The decrease in carbidopa of tolcapone treatment and might be a reflection of the limited number of samples available for each dosing interval.…”

mentioning

confidence: 87%

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

Jorga

Nicholl

1999

Brit J Clinical Pharma

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Aims Tolcapone is a novel catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/carbidopa or levodopa/benserazide therapy to improve treatment of Parkinson's disease. The aim of the current study was to investigate the potential effect of tolcapone on the pharmacokinetics of carbidopa. MethodsThis was an open-label study in 12 parkinsonian patients receiving optimal levodopa/carbidopa therapy and tolcapone 200 mg three times daily for 6 weeks. Blood samples were taken at baseline (i.e. before the first tolcapone intake) and after 1-2 weeks and 6 weeks so that carbidopa pharmacokinetics before and during tolcapone treatment could be assessed. Results No changes in any pharmacokinetic parameters of carbidopa were observed. The mean AUC(0,t) and C max values at baseline were 0.39 mg ml −1 h and 0.14 mg ml −1, respectively. During tolcapone treatment these values were on average 0.35 mg ml −1 h (AUC(0,t), week 1-2), 0.34 mg ml −1 h (AUC(0,t), week 6 and 0.13 mg ml −1 (C max , weeks 1-2 and 6). t max remained unchanged (approx. 2 h). ConclusionsThese results indicate that tolcapone does not affect carbidopa elimination and that no interaction of any clinical relevance occurs between tolcapone and carbidopa.

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“…Half of the maximum inhibition was attained at tolcapone plasma concentrations of about 1 mg/liter. Co-administration of levodopa formulations does not influence the inhibitory effects of entacapone or tolcapone on erythrocyte COMT activity [Dingemanse et al, 1995a,b;Ahtila et al, 1995]. The COMT inhibitory effects are sustained upon multiple dosing, but the level of inhibition varies widely when the drug is administered t.i.d.…”

Section: Pharmacodynamics Effect On Erythrocyte Comt Activitymentioning

confidence: 99%

“…decreased 3-OMD plasma concentrations by 43% [Bieck et al, 1993;Antonin et al, 1991]. The change in 3-OMD levels can be predicted from COMT activity in erythrocytes [Dingemanse et al, 1995a;Jorga et al, 1993;Ahtila et al, 1995].…”

Section: Effect On 3-omd Pharmacokineticsmentioning

confidence: 99%

Catechol-O-methyltransferase inhibitors: Clinical potential in the treatment of Parkinson's disease

Dingemanse¹

1997

Drug Dev. Res.

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Effect of Entacapone, a COMP Inhibitor, on the Pharmacokinetics and Metabolism of Levodopa After Administration of Controlled-Release Levodopa-Carbidopa in Volunteers

Cited by 53 publications

References 0 publications

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

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

Catechol-O-methyltransferase inhibitors: Clinical potential in the treatment of Parkinson's disease

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