DRUG INTERACTIONS Drug Interactions
Protein Binding: Although tolcapone is highly protein bound, in vitro studies have shown that tolcapone at a concentration of 50 µg/mL did not displace other highly protein-bound drugs from their binding sites at therapeutic concentrations. The experiments included warfarin (0.5 to 7.2 µg/mL), phenytoin (4.0 to 38.7 µg/mL), tolbutamide (24.5 to 96.1 µg/mL) and digitoxin (9.0 to 27.0 µg/mL).
Drugs Metabolized by Catechol-O-Methyltransferase (COMT): Tolcapone may influence the pharmacokinetics of drugs metabolized by COMT. However, no effects were seen on the pharmacokinetics of the COMT substrate carbidopa. The effect of tolcapone on the pharmacokinetics of other drugs of this class such as á-methyldopa, dobutamine, apomorphine, and isoproterenol has not been evaluated. A dose reduction of such compounds should be considered when they are coadministered with tolcapone.
Effect of Tolcapone on the Metabolism of Other Drugs: In vitro experiments have been performed to assess the potential of tolcapone to interact with isoenzymes of cytochrome P450 (CYP). No relevant interactions with substrates for CYP 2A6 (coumadin), CYP 1A2 (caffeine), CYP 3A4 (midazolam, terfenadine, cyclosporine), CYP 2C19 (S-mephenytoin) and CYP 2D6 (desipramine) were observed in vitro. The absence of an interaction with desipramine, a drug metabolized by cytochrome P450 2D6, was also confirmed in an in vivo study where tolcapone did not change the pharmacokinetics of desipramine.
Due to its affinity to cytochrome P450 2C9 in vitro, tolcapone may interfere with drugs, whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin. However, in an in vivo interaction study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome P450 2C9 appear unlikely. Similarly, tolcapone did not affect the pharmacokinetics of desipramine, a drug metabolized by cytochrome P450 2D6, indicating that interactions with drugs metabolized by that enzyme are unlikely. Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation parameters should be monitored when these two drugs are coadministered.
Drugs That Increase Catecholamines: Tolcapone did not influence the effect of ephedrine, an indirect sympathomimetic, on hemodynamic parameters or plasma catecholamine levels, either at rest or during exercise. Since tolcapone did not alter the tolerability of ephedrine, these drugs can be coadministered.
When TASMAR was given together with levodopa/carbidopa and desipramine, there was no significant change in blood pressure, pulse rate and plasma concentrations of desipramine. Overall, the frequency of adverse events increased slightly. These adverse events were predictable based on the known adverse reactions to each of the three drugs individually. Therefore, caution should be exercised when desipramine is administered to Parkinson’s disease patients being treated with TASMAR and levodopa/carbidopa.
In clinical trials, patients receiving TASMAR/levodopa preparations reported a similar adverse event profile independent of whether or not they were also concomitantly administered selegiline (a selective MAO-B inhibitor).
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OVERDOSAGE
The highest dose of tolcapone administered to humans was 800 mg tid, with and without levodopa/carbidopa coadministration. This was in a 1-week study in elderly, healthy volunteers. The peak plasma concentrations of tolcapone at this dose were on average 30 µg/mL (compared to 3 µg/mL and 6 µg/mL with 100 mg and 200 mg tolcapone, respectively). Nausea, vomiting and dizziness were observed, particularly in combination with levodopa/carbidopa.
The threshold for the lethal plasma concentration for tolcapone based on animal data is >100 µg/mL. Respiratory difficulties were observed in rats at high oral (gavage) and intravenous doses and in dogs with rapidly injected intravenous doses.
Management of Overdose: Hospitalization is advised. General supportive care is indicated. Based on the physicochemical properties of the compound, hemodialysis is unlikely to be of benefit.
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