Species-Dependent Citrus–Simvastatin Interaction Profiles in an Acute Rat Model: Integrating Drug Disposition, Hepatic Redox, and Complementary Computational Analysis

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Citrus species differ widely in flavonoid chemistry, yet grapefruit has come to represent the genus in citrus–statin interactions. To test whether this translates into species-dependent interaction profiles, six flavonoid-profiled citrus peel extracts (Citrus limon, C. depressa Hayata, C. maxima, C. × paradisi, C. × sinensis, and C. reticulata) were compared in a standardized acute rat model spanning drug disposition, CYP3A and transporter systems, hepatic redox status, and in silico analysis. The naringin-dominated C. × paradisi produced the most coordinated disruption of CYP3A and transporter pathways, raising plasma simvastatin acid at 1 h by 506% versus the simvastatin-only group, together with the least favorable redox profile. The polymethoxyflavone-rich C. depressa Hayata perturbed disposition mildly yet raised the hepatic GSH/GSSG ratio by 227%. Hepatic active-metabolite accumulation was therefore uncoupled from redox outcome, indicating that disposition and redox response are separable axes and that grapefruit cannot represent the citrus genus.