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In the past decades, rising safety concerns about drug-induced phospholipidosis (DIPL) have induced scientists to develop novel strategies to detect the risk of DIPL early in drug discovery and drug development. An early detection of phospholipidosis (PL)-inducing potential of new chemical entities will contribute to the release of safer drugs, also reducing associated investments and time. This chapter focuses on concisely summarizing the current knowledge on DIPL, from the chemical features that are compatible with warnings to the proposed mechanisms behind phospholipid accumulation. In addition, strategies to mitigate the risk of DIPL are discussed.

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