Assessing CYP2C8-Mediated Pharmaceutical Excipient-Drug Interaction Potential: A Case Study of Tween 80 and Cremophor EL−35
Chengming Wen,
Haoyang Hu,
Wenwen Zhang,
Xin Liu,
Xuehua Jiang,
Ling Wang
Affiliations
Chengming Wen
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Haoyang Hu
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Wenwen Zhang
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Xin Liu
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Xuehua Jiang
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Ling Wang
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Pharmaceutical excipients (PEs) are substances included in drug formulations. Recent studies have revealed that some PEs can affect the activity of metabolic enzymes and drug transporters; however, the effects of PEs on CYP2C8 and its interaction potential with drugs remain unclear. In this study, we evaluated the effects of Tween 80 and EL−35 on CYP2C8 in vitro and further investigated their impacts on the PK of paclitaxel (PTX) in rats after single or multiple doses. The in vitro study indicated that Tween 80 and EL−35 inhibited CYP2C8 activity in human and rat liver microsomes. EL−35 also decreased the expression of CYP2C8 in HepG2 cells. In the in vivo study, Tween 80 did not alter the PK of PTX after single or multiple doses, whereas EL−35 administered for 14 days significantly increased the AUC and MRT of PTX. Further analysis indicated that multiple-dose EL−35 reduced the expression of Cyp2c22 and production of 6-OH-PTX in the rat liver. Our study suggested that short-term exposure to both PEs did not affect the PK of PTX in rats, but multiple doses of EL−35 increased the AUC and MRT of PTX by downregulating the hepatic expression of Cyp2c22. Such effects should be taken into consideration during drug formulation and administration.
