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The active enantiomer R-Praziquantel (PZQ) shows clinically a lower relative exposure when administered enantiomerically pure compared to a racemic form. We investigated the hypothesis that enantiomer-enantiomer interactions on CYP enzymes could explain this observation and aimed to further deepen the understanding of PZQ metabolism. Firstly, in an in vitro metabolite profiling study, the formation of multiple metabolites per CYP, together with an observed interconversion of cis-4'-OH-PZQ to trans-4'-OH-PZQ in human hepatocytes, pointed out the inadequacy of measuring metabolite formation in kinetic studies. Thus, a substrate depletion approach to study PZQ enantiomeric interactions was applied. Secondly, an abundant CYP 3A4 metabolite found in previous studies was structurally characterized. Thirdly, substrate depletion methodologies were applied to determine CYP enzyme kinetics of PZQ and to further estimate enantiomer-enantiomer inhibitory parameters. A competitive inhibition between PZQ enantiomers for CYP2C9, 2C19, 3A4 and 3A5 was revealed. Analyses considering the clearance of only one or both enantiomers provided comparable enantiomer-enantiomer inhibition estimates. To conclude, this paper provides new insights into PZQ metabolic profile to enable a better understanding of enantioselective PK using substrate depletion-based methods. Significance Statement In this study, enantiomer-enantiomer interactions of praziquantel on CYP metabolizing enzymes are investigated via substrate depletion measurement using modelling methods. Together with new insights into the praziquantel metabolism, this work provides a novel dataset to understand its pharmacokinetics.