Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone With DILIsym ???? , a Mechanistic Model of Drug?￠????Induced Liver Injury

摘要

Tolcapone and entacapone are catechol?￠????O?￠????methyltransferase (COMT) inhibitors developed as adjunct therapies for treating Parkinson's disease. While both drugs have been shown to cause mitochondrial dysfunction and inhibition of the bile salt export protein (BSEP), liver injury has only been associated with the use of tolcapone. Here we used a multiscale, mechanistic model (DILIsym ???? ) to simulate the response to tolcapone and entacapone. In a simulated population (SimPops?￠???￠) receiving recommended doses of tolcapone (200 mg t.i.d.), increases in serum alanine transaminase (ALT) >3???? the upper limit of normal (ULN) were observed in 2.2% of the population. In contrast, no simulated patients receiving recommended doses of entacapone (200 mg 8???? day) experienced serum ALT >3???? ULN. Further, DILIsym ???? analyses revealed patient?￠????specific risk factors that may contribute to tolcapone?￠????mediated hepatotoxicity. In summary, the simulations demonstrated that differences in mitochondrial uncoupling potency and hepatic exposure primarily account for the difference in hepatotoxic potential for tolcapone and entacapone.