Assessment of drug-induced hepatotoxicity considering drug metabolism and pharmacokinetics by hepatocyte spheroids and chimeric mice with humanized liver

Abstract

We observed that acetaminophen induced CYP by inhibition of the proteolysis, and phospholipid accumulation by metabolic activation of loratadine in hepatocyte spheroids. On the other hand, we have evaluated drug-induced phospholipidosis by amiodarone, and cholestasis by rifampicin in chimeric mice with humanized liver. It may also be useful for assessment of drug-induced steatosis. Furthermore, it can be used for estimation of safety margin because PK could be predicted by chimeric mice. It is expected that combination of the in vitro and in vivo evaluation can contribute to drug discovery.