BIA 3-202, a Novel Catechol-O-Methyltransferase Inhibitor, Reduces the Peripheral O-Methylation of &lt;i&gt;L&lt;/i&gt;-DOPA and Enhances Its Availability to the Brain

Parada, António; Soares-da-Silva, Patrı́cio

doi:10.1159/000068730

Cited by 12 publications

(8 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This also occurs with other COMT inhibitors such as nebicapone, which can cause peripheral and central COMT inhibition in vivo, despite having been herein identified as a BCRP substrate. Nebicapone displays a dose-dependent central COMT inhibitory effect since peripheral selectivity is observed at 3 mg/kg but lost at 30 mg/kg following oral administration in Wistar rats (Parada and Soares-da-Silva, 2003).…”

Section: Test Compoundmentioning

confidence: 99%

“…Currently, there are three COMT inhibitors available in the market: entacapone; tolcapone, only used in patients unresponsive to other treatments and with monitoring of liver function; and opicapone, since its recent approval by the European Medicines Agency in June 2016 (Kiss and Soares-da-Silva, 2014;Annus and Vécsei, 2017). The peripheral (BIA 9-1059, BIA 9-1079, entacapone, and opicapone) and/or central (nebicapone and tolcapone) enzymatic inhibition displayed by these compounds justify the investigation of the role that P-gp and/or BCRP may have in their access to the CNS (Learmonth et al, 2002;Napolitano et al, 2003;Parada and Soares-da-Silva, 2003;Kiss et al, 2008;Bonifácio et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

Bicker

Fortuna

Alves

et al. 2017

Drug Metabolism and Disposition

Self Cite

View full text Add to dashboard Cite

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are clinically important efflux transporters that act cooperatively at the blood-brain barrier, limiting the entry of several drugs into the central nervous system (CNS) and affecting their pharmacokinetics, therapeutic efficacy, and safety. In the present study, the interactions of catechol--methyltransferase (COMT) inhibitors (BIA 9-1059, BIA 9-1079, entacapone, nebicapone, opicapone, and tolcapone) with P-gp and BCRP were investigated to determine the contribution of these transporters in their access to the brain. In vitro cellular accumulation and bidirectional transport assays were conducted in Madin-Darby canine kidney (MDCK) II, MDCK-MDR1, and MDCK-BCRP cells. In vivo pharmacokinetic studies were carried out for tolcapone and BIA 9-1079 in rats, with and without elacridar, a well-known P-gp and BCRP modulator. The results suggest that BIA 9-1079, nebicapone, and tolcapone inhibit BCRP in a concentration-dependent manner. Moreover, with net flux ratios higher than 2 and decreased over 50% in the presence of verapamil or Ko143, BIA 9-1079 was identified as a P-gp substrate while BIA 9-1059, entacapone, opicapone, and nebicapone were revealed to be BCRP substrates. In vivo, brain exposure was limited for tolcapone and BIA 9-1079, although tolcapone crossed the blood-brain barrier at a greater rate and to a greater extent than BIA 9-1079. The extent of brain distribution of both compounds was significantly increased in the presence of elacridar, attesting to the involvement of efflux transporters. These findings provide relevant information and improve the understanding of the mechanisms that govern the access of these COMT inhibitors to the CNS.

show abstract

Section: Test Compoundmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

Bicker

Fortuna

Alves

et al. 2017

Drug Metabolism and Disposition

Self Cite

View full text Add to dashboard Cite

show abstract

“…SAM has been claimed to have an antidepressant role (Zurcher et al 1993) and, therefore, it was suggested that this SAM‐sparing effect could be of some advantage in treating patients afflicted with PD, who often show symptoms of depression (Da Prada et al 1994). On the other hand, inhibition of peripheral COMT is shown to be sufficient to increase the amount of levodopa reaching the brain, by protecting its O ‐methylation in the periphery (Linden et al 1988; Nissinen et al 1992; Parada and Soares‐da‐Silva 2003). Therefore, COMT inhibitors with limited access to the brain may serve as effective adjunct therapy of PD, while avoiding potential undesired central side effects.…”

Section: Comt Inhibitorsmentioning

confidence: 99%

Catechol‐O‐methyltransferase and Its Inhibitors in Parkinson's Disease

et al. 2007

Self Cite

View full text Add to dashboard Cite

Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of dopaminergic neurons, with consequent reduction in striatal dopamine levels leading to characteristic motor symptoms. The most effective treatment for this disease continues to be the dopamine replacement therapy with levodopa together with an inhibitor of aromatic amino acid decarboxylase (AADC). The efficacy of this therapy, however, decreases with time and most patients develop fluctuating responses and dyskinesias. The last decade showed that the use of catechol-O-methyltransferase inhibitors as adjuvants to the levodopa/AADC inhibitor therapy, significantly improves the clinical benefits of this therapy.The purpose of this article is to review the current knowledge on the enzyme catechol-O-methyltransferase (COMT) and the role of COMT inhibitors in PD as a new therapeutic approach to PD involving conversion of levodopa to dopamine at the target region in the brain and facilitation of the continuous action of this amine at the receptor sites. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on nebicapone, presently under clinical development, as well as entacapone and tolcapone, which are already approved as adjuncts in the therapy of PD. This article reviews human pharmacokinetic and pharmacodynamic properties of these drugs as well as their clinical efficacy and safety.

show abstract

“…At t max , inhibition of liver COMT was similar for BIA 3-202 and tolcapone, but BIA 3-202 was clearly less potent than tolcapone in inhibiting brain COMT [14]. In several animal models, concomitant administration of BIA 3-202 with levodopa plus benserazide increased in a time-and dose-dependent manner the availability of levodopa to the brain, this being accompanied with increases in plasma levodopa AUC values [15,16,17]. In an entry-into-man study in healthy male subjects, single doses of 10-800 mg BIA 3-202 were well tolerated [18].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic?pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/benserazide

Silveira

Vaz‐da‐Silva

Almeida

et al. 2003

European Journal of Clinical Pharmacology

View full text Add to dashboard Cite

BIA 3-202 is a novel catechol-O-methyltransferase (COMT) inhibitor being developed for use as a levodopa-sparing agent in Parkinson's disease. This study investigated the effect of four single oral doses of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg) compared with placebo on plasma concentrations of levodopa and its metabolite 3- O-methyl-levodopa (3-OMD) and on inhibition of erythrocyte COMT in healthy subjects receiving 100 mg of levodopa and 25 mg of benserazide (Madopar 125). This was a single-centre, double-blind, placebo-controlled, randomised, crossover study with five single-dose treatment periods. The washout period between doses was 2 weeks. On each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Madopar 125. Tolerability was assessed by recording adverse events, vital signs, continuous electrocardiogram and clinical laboratory parameters. In the study, 18 subjects (12 male and 6 female) participated. The drug combination was well tolerated. All doses of BIA 3-202 significantly increased the area under the concentration-time curve (AUC) versus placebo, ranging from 39% (95% confidence intervals, 1.06-1.69) with 50 mg to 80% (95% confidence intervals, 1.42-2.22) with 400 mg. No significant change in mean maximum plasma concentrations (C(max)) of levodopa was found. Mean C(max) and AUC of 3-OMD significantly decreased for all doses tested. BIA 3-202 caused a rapid and reversible inhibition of S-COMT activity, ranging from 57% (50 mg) to 84% (400 mg). In conclusion, the novel COMT inhibitor BIA 3-202 was well tolerated and significantly increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard release levodopa/benserazide.

show abstract

BIA 3-202, a Novel Catechol-O-Methyltransferase Inhibitor, Reduces the Peripheral O-Methylation of <i>L</i>-DOPA and Enhances Its Availability to the Brain

Cited by 12 publications

References 19 publications

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

Catechol‐O‐methyltransferase and Its Inhibitors in Parkinson's Disease

Pharmacokinetic?pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/benserazide

Contact Info

Product

Resources

About