Evaluation of Luteolin Nanosuspensions on Pharmacokinetics of Atorvastatin: Drug-Drug Interactions Using Rat Models

The co-administration of luteolin (LUT) and atorvastatin (ATV) may drive synergetic effects on against atherosclerotic cardiovascular disease (ASCVD). This study aims to explore the pharmacokinetic (PK) drug-drug interactions (DDIs) of LUT toward ATV and the influencing mechanisms involving CYP450s and OATPs, and using the physiologically based pharmacokinetic (PBPK) models extrapolated to humans to optimize the DDIs dosage regimens for subsequent research.

Luteolin nanosuspensions lyophilized powder (LUT-NS-LP) were prepared for improving LUT's solubility and bioavailability, the effects of both LUT on the ATV CYP450s enzyme kinetics and LUT-NS-LP/LUT on the PK behavior of ATV in rats were further studied by UPLC. The DDI PBPK model of ATV and LUT-NS-LP was established with the hepatic CYP450s, OATPs, and enterohepatic circulation, and extrapolated to humans through a physiological allometric scaling process with parameter optimization and verified using clinical datasets obtained from various dosage regimens.

LUT inhibited ATV as the non-competitive form in rat liver microsomes (RLMs). The C _max and AUC _(0-t) of ATV in the group receiving combined administration of LUT and LUT-NS-LP increased by 1.87-fold and 2.29-fold, 5.42-fold and 10.35-fold, respectively. The constructed PBPK models successfully predicted the PK DDIs between ATV and LUT in rats, demonstrating excellent performance. LUT might inhibit the hepatic CYP450s and OATPs activities to influence the PK behavior of ATV. The extrapolated human model could adequately describe and predict the systemic exposure of ATV in DDIs.

LUT nanosuspensions could significantly increase systemic exposure to ATV by inhibiting CYP450s and OATPs activities. The combined application strategy is suggested to run ATV in half of the highest dosage by guidelines. This study offers a valuable experimental foundation for the combined administration of statins with natural drugs and their nanoformulations, providing significant insights into the investigation of underlying mechanisms and potential clinical applications.