The cytotoxicities of 12 non-steroidal anti-inflammatory drugs (NSAIDs) in primary monolayer cultures of rat hepatocytes were compared. Toxicity was determined by measuring the release of lactate dehydrogenase into the culture medium after 20 hr of exposure. Diflunisal was the most cytotoxic, followed, in order, by mefenamic acid, diclofenac, indomethacin, flurbiprofen, piroxicam, sulindac and ibuprofen. Ketoprofen, naproxen, tolmetin and acetylsalicylic acid (ASA) were the least cytotoxic. Phenobarbital pretreatment in vivo potentiated the in vitro toxicity of diclofenac, ketoprofen and piroxicam, and SKF525-A addition to the medium reduced their toxicity. These results indicate that the cytocidal hepatotoxicity of diclofenac, ketoprofen and piroxicam may be mediated, at least partially, by cytochrome P-450 metabolism. The cytotoxicity of the other nine NSAIDs appears not to be significantly influenced by cytochrome P450 modulation.
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