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

Abstract 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.