COMT inhibitors and liver toxicity.
This paper reviews the issue of hepatotoxicity with the use of the catechol-O-methly transferase (COMT) inhibitors tolcapone and entacapone. Neither drug caused hepatotoxicity in preclinical toxicity testing. However, in clinical trials of tolcapone, liver chemistry tests were elevated more than 3 times above the upper limit of normal in approximately 1% of patients who took the 100 mg dose and in approximately 3% of patients who took the 200 mg dose. These observations led to the recommendation that periodic monitoring of liver function be performed. Post-marketing surveillance studies noted 3 instances of acute liver failure with death after 60,000 patients had received tolcapone for a total of 40,000 patient-years. For this reason, the drug was withdrawn from the market in Europe and Canada, and a black box warning issued in the United States. In contrast, clinical trials with entacapone demonstrated no increase in liver enzymes above those observed with placebo. Further, no instances of acute liver failure or death attributed to the drug have been observed in post-marketing surveillance studies. Consequently, liver monitoring is not required with this agent. These data demonstrate that tolcapone is associated with a risk of hepatotoxicity but that no such risk has been detected with entacapone.
Watkins
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University of North Carolina at Chapel Hill School of Medicine, 27599, USA.
D001577:Benzophenones / Q000009:adverse effects* / Q000627:therapeutic use*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000009:adverse effects* / Q000627:therapeutic use*; D006801:Humans; D008099:Liver / Q000187:drug effects*; D009570:Nitriles; D009596:Nitrophenols; D010300:Parkinson Disease / Q000188:drug therapy*; D000077867:Tolcapone
D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; C071192:entacapone; D000077867:Tolcapone