Hepatotoxicity and metabolism of trabectedin: a literature review.
Trabectedin is a promising anticancer drug currently undergoing phase II evaluation. In preclinical studies, trabectedin was found to cause hepatotoxicity and in patients it reversibly increases plasma levels of liver enzymes. On the basis of preclinical work, it was suggested that metabolism of trabectedin contributed to the pharmacological effects of trabectedin, including hepatotoxicity in rats and increases in liver enzymes in humans. Our aim was to review the current literature on the metabolism of trabectedin and its role in the increases in liver enzymes and hepatotoxicity. We conclude that the trabectedin metabolic profile appears to predict the reversible nature of hepatotoxicity. The rat may not be the best species to investigate trabectedin hepatotoxicity because both trabectedin metabolic profile and reversibility of hepatotoxicity differs from humans. Humans and monkeys display a similar metabolic profile of trabectedin and in both species hepatotoxicity is reversible. Trabectedin is a drug with predictable hepatotoxic effects. Monitoring of plasma levels of liver enzymes ensures safe use of trabectedin in the clinic. Future investigations must be aimed at elucidating the mechanism of trabectedin hepatotoxicity.
Beumer
J H
JH
Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. apjbe@slz.nl
Schellens
J H M
JH
Beijnen
J H
JH
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004149:Dioxoles / Q000009:adverse effects* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects* / Q000378:metabolism*; D051381:Rats; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D000970:Antineoplastic Agents; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin