You Liang,* Bo Sun,* Min Yang, Xiaona Meng, Meng Wang, Lijuan Yang, Bandar AI-Hamyari, Yuqian Zhang, Yutong Shen, Shengnan Meng

Department of Pharmaceutics, School of Pharmacy, China Medical University, Shenyang, 110122, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Shengnan Meng, Department of Pharmaceutics, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, People’s Republic of China, Tel +86 024 31939448, Email snmeng@cmu.edu.cn

Purpose: 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.
Methods: 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.
Results: LUT inhibited ATV as the non-competitive form in rat liver microsomes (RLMs). The Cmax 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.
Conclusion: 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.
Plain Language Summary: In this study, we focused on how luteolin (LUT), a natural compound, interacts with atorvastatin (ATV), a commonly used drug for heart disease. We wanted to understand whether taking these two compounds together could alter ATV’s absorption and breakdown, which potentially influences its effectiveness and safety.
To improve LUT’s ability to work in the body, we prepared a special form that dissolves more easily, and tested how LUT impacted ATV’s behavior in rats and used advanced computer models to predict what might happen in humans.
We found that the cooperation of LUT and ATV, LUT significantly increased the levels of ATV in the bloodstream. This happens because LUT slows down the liver’s ability to dispose of ATV, leading to higher levels of the drug in the body. We confirmed these results in rats, and the computer models also supported the findings.
This study offers evidence that when LUT is combined with ATV, LUT increases the amount of ATV in the bloodstream, and a promising strategy by computer predictions for humans is that the dosage of ATV need to be adjusted to avoid potential side effects. Our research offers valuable insights into how natural compounds like LUT could be used alongside medications to improve treatments for heart disease in the future.

Keywords: luteolin, atorvastatin, drug-drug interactions, nanosuspension, PBPK, atherosclerotic cardiovascular disease