Utility of tolcapone in fluctuating Parkinson's disease

Abstract

Fluctuating Parkinson’s disease (PD) represents a clinical management challenge. The primary utility of levodopa in patients with PD is moderated by the “wearing off” phenomena seen with long-term use. COMT inhibitors slow down the rapid metabolism of levodopa, resulting in a more-sustained response to dopaminergic therapy. Tolcapone is a selective, reversible catechol-O-methyltransferase (COMT) inhibitor, shown to have both peripheral and central effects. In clinical trials, tolcapone has been shown to reduce “off” time, increase “on” time, improve patient and clinician assessments of disease severity, and improve patient quality of life. In a SWITCH study, tolcapone was associated with greater duration of “on” time than remaining on entacapone. Adverse effects of tolcapone are related to the class, with the exception of rare cases of hepatotoxicity. Tolcapone has been recently reintroduced on the European market and recent guidance from the US Food and Drug Administration has reduced the hepatic monitoring requirements for patients initiating tolcapone therapy. With proper monitoring, tolcapone is an effective, well-tolerated drug useful in the management of patients with fluctuating PD.

Analytical and Computational Insights Into Serum Albumin Interactions with Antiparkinsonian Drugs: A Comprehensive Review

“…[123] For example, tolcapone, a potent COMT inhibitor with >99.9% serum albumin binding, exhibits limited volume of distribution and rapid hepatic clearance via glucuronidation and mitochondrial oxidation, demonstrating that extensive binding does not preclude efficient elimination when metabolic capacity is high. [107,108,124] Another illustrative case is rotigotine, which is delivered transdermally and exhibits high serum albumin binding (89%-92%). Despite this, it attains an exceptionally large volume of distribution (>2500 L), attributable to both its high lipophilicity and the depot effect from dermal reservoirs.…”

“…For example, tolcapone, a potent COMT inhibitor with >99.9% serum albumin binding, exhibits limited volume of distribution and rapid hepatic clearance via glucuronidation and mitochondrial oxidation, demonstrating that extensive binding does not preclude efficient elimination when metabolic capacity is high. [ 107,108,124 ]…”

Analytical and Computational Insights Into Serum Albumin Interactions with Antiparkinsonian Drugs: A Comprehensive Review

“…[123] For example, tolcapone, a potent COMT inhibitor with >99.9% serum albumin binding, exhibits limited volume of distribution and rapid hepatic clearance via glucuronidation and mitochondrial oxidation, demonstrating that extensive binding does not preclude efficient elimination when metabolic capacity is high. [107,108,124] Another illustrative case is rotigotine, which is delivered transdermally and exhibits high serum albumin binding (89%-92%). Despite this, it attains an exceptionally large volume of distribution (>2500 L), attributable to both its high lipophilicity and the depot effect from dermal reservoirs.…”

“…For example, tolcapone, a potent COMT inhibitor with >99.9% serum albumin binding, exhibits limited volume of distribution and rapid hepatic clearance via glucuronidation and mitochondrial oxidation, demonstrating that extensive binding does not preclude efficient elimination when metabolic capacity is high. [ 107,108,124 ]…”

Chromone: A Valid Scaffold in Medicinal Chemistry

“…Tolcapone has a half-life similar to entacapone but, as it has a greater bioavailability and smaller volume of distribution, thus resulting in higher potency for COMT inhibition [54] . Furthermore, tolcapone, unlike entacapone, may also inhibit central COMT brain [67,68] , increasing peripherally and central L-dopa availability, thus enhancing striatum dopamine neurotransmission [68] . However, the appearance of fatal acute hepatitis in some patients receiving tolcapone, raised several concerns about this drug and the European Medicines Agency (EMEA) has temporary suspended tolcapone in the European Union (EU) [67,69] .…”

“…Furthermore, tolcapone, unlike entacapone, may also inhibit central COMT brain [67,68] , increasing peripherally and central L-dopa availability, thus enhancing striatum dopamine neurotransmission [68] . However, the appearance of fatal acute hepatitis in some patients receiving tolcapone, raised several concerns about this drug and the European Medicines Agency (EMEA) has temporary suspended tolcapone in the European Union (EU) [67,69] . In 2004, EMEA lift the suspension but its use was substantially curtailed [67] .…”

“…However, the appearance of fatal acute hepatitis in some patients receiving tolcapone, raised several concerns about this drug and the European Medicines Agency (EMEA) has temporary suspended tolcapone in the European Union (EU) [67,69] . In 2004, EMEA lift the suspension but its use was substantially curtailed [67] . Comparatively, entacapone does not show the same tendency to cause hepatotoxicity, being the most common side effects related with the dopaminergic system.…”

Analytical and Computational Insights Into Serum Albumin Interactions with Antiparkinsonian Drugs: A Comprehensive Review

“…[123] For example, tolcapone, a potent COMT inhibitor with >99.9% serum albumin binding, exhibits limited volume of distribution and rapid hepatic clearance via glucuronidation and mitochondrial oxidation, demonstrating that extensive binding does not preclude efficient elimination when metabolic capacity is high. [107,108,124] Another illustrative case is rotigotine, which is delivered transdermally and exhibits high serum albumin binding (89%-92%). Despite this, it attains an exceptionally large volume of distribution (>2500 L), attributable to both its high lipophilicity and the depot effect from dermal reservoirs.…”

“…For example, tolcapone, a potent COMT inhibitor with >99.9% serum albumin binding, exhibits limited volume of distribution and rapid hepatic clearance via glucuronidation and mitochondrial oxidation, demonstrating that extensive binding does not preclude efficient elimination when metabolic capacity is high. [ 107,108,124 ]…”

Chromone: A Valid Scaffold in Medicinal Chemistry

“…Tolcapone has a half-life similar to entacapone but, as it has a greater bioavailability and smaller volume of distribution, thus resulting in higher potency for COMT inhibition [54] . Furthermore, tolcapone, unlike entacapone, may also inhibit central COMT brain [67,68] , increasing peripherally and central L-dopa availability, thus enhancing striatum dopamine neurotransmission [68] . However, the appearance of fatal acute hepatitis in some patients receiving tolcapone, raised several concerns about this drug and the European Medicines Agency (EMEA) has temporary suspended tolcapone in the European Union (EU) [67,69] .…”

“…Furthermore, tolcapone, unlike entacapone, may also inhibit central COMT brain [67,68] , increasing peripherally and central L-dopa availability, thus enhancing striatum dopamine neurotransmission [68] . However, the appearance of fatal acute hepatitis in some patients receiving tolcapone, raised several concerns about this drug and the European Medicines Agency (EMEA) has temporary suspended tolcapone in the European Union (EU) [67,69] . In 2004, EMEA lift the suspension but its use was substantially curtailed [67] .…”

“…However, the appearance of fatal acute hepatitis in some patients receiving tolcapone, raised several concerns about this drug and the European Medicines Agency (EMEA) has temporary suspended tolcapone in the European Union (EU) [67,69] . In 2004, EMEA lift the suspension but its use was substantially curtailed [67] . Comparatively, entacapone does not show the same tendency to cause hepatotoxicity, being the most common side effects related with the dopaminergic system.…”

Analytical and Computational Insights Into Serum Albumin Interactions with Antiparkinsonian Drugs: A Comprehensive Review

“…[123] For example, tolcapone, a potent COMT inhibitor with >99.9% serum albumin binding, exhibits limited volume of distribution and rapid hepatic clearance via glucuronidation and mitochondrial oxidation, demonstrating that extensive binding does not preclude efficient elimination when metabolic capacity is high. [107,108,124] Another illustrative case is rotigotine, which is delivered transdermally and exhibits high serum albumin binding (89%-92%). Despite this, it attains an exceptionally large volume of distribution (>2500 L), attributable to both its high lipophilicity and the depot effect from dermal reservoirs.…”

“…For example, tolcapone, a potent COMT inhibitor with >99.9% serum albumin binding, exhibits limited volume of distribution and rapid hepatic clearance via glucuronidation and mitochondrial oxidation, demonstrating that extensive binding does not preclude efficient elimination when metabolic capacity is high. [ 107,108,124 ]…”

Chromone: A Valid Scaffold in Medicinal Chemistry

“…Tolcapone has a half-life similar to entacapone but, as it has a greater bioavailability and smaller volume of distribution, thus resulting in higher potency for COMT inhibition [54] . Furthermore, tolcapone, unlike entacapone, may also inhibit central COMT brain [67,68] , increasing peripherally and central L-dopa availability, thus enhancing striatum dopamine neurotransmission [68] . However, the appearance of fatal acute hepatitis in some patients receiving tolcapone, raised several concerns about this drug and the European Medicines Agency (EMEA) has temporary suspended tolcapone in the European Union (EU) [67,69] .…”

“…Furthermore, tolcapone, unlike entacapone, may also inhibit central COMT brain [67,68] , increasing peripherally and central L-dopa availability, thus enhancing striatum dopamine neurotransmission [68] . However, the appearance of fatal acute hepatitis in some patients receiving tolcapone, raised several concerns about this drug and the European Medicines Agency (EMEA) has temporary suspended tolcapone in the European Union (EU) [67,69] . In 2004, EMEA lift the suspension but its use was substantially curtailed [67] .…”

“…However, the appearance of fatal acute hepatitis in some patients receiving tolcapone, raised several concerns about this drug and the European Medicines Agency (EMEA) has temporary suspended tolcapone in the European Union (EU) [67,69] . In 2004, EMEA lift the suspension but its use was substantially curtailed [67] . Comparatively, entacapone does not show the same tendency to cause hepatotoxicity, being the most common side effects related with the dopaminergic system.…”