Effect of vorinostat on P-gp expression and pharmacokinetic parameters of its substrate phenytoin sodium in rats under hypoxic environments
- VernacularTitle:低氧环境下伏立诺他对大鼠体内P-gp表达及其底物苯妥英钠药代参数的影响
- Author:
Zi-qin WEI
1
;
Hong-fang MU
;
Lin JIANG
;
Fang-fang QIU
;
Dou-dou LI
;
Wen-bin LI
;
Rong WANG
Author Information
- Publication Type:Journal Article
- Keywords: hypoxia; SAHA; P-gp; HDAC5; pheny-toin sodium; pharmacokinetics
- From: Chinese Pharmacological Bulletin 2025;41(12):2291-2297
- CountryChina
- Language:Chinese
- Abstract: Aim To investigate the effects of SAHA on the expression of P-gp and the pharmacokinetic pa-rameters of its substrate phenytoin sodium in rats under hypoxic environments.Methods Wistar rats were randomly divided into the normioxic group,the hypoxic model group,and the low-,medium-and high-dose vorinostat(SAHA)groups.Liver tissues were col-lected,and the expression levels of P-gp and HDAC5 were detected by Real-time PCR and Western blot.The morphological changes of liver tissues were ob-served by HE staining.Following intragastric adminis-tration of 50 mg·kg-1 phenytoin sodium to each group,blood samples were collected,and the plasma concentration of phenytoin sodium was determined u-sing UFLC-MS/MS to calculate pharmacokinetic pa-rameters.Results Compared with the normoxic group,the expression of HDAC5 in the liver tissues of hypoxia model rats increased,while the expression of P-gp decreased.After SAHA treatment,HDAC5 expression decreased,and P-gp expression increased.Among the SAHA groups,the medium-dose group showed the most significant effect,and HE staining re-sults indicated that this concentration did not cause damage to rat liver tissues.Compared with the normox-ic group,the AUC,Cmax,and T1/2 of phenytoin sodium in hypoxia model rats were significantly raised.After administration of the medium dose of SAHA,the AUC,Cmax,MRT,and T1/2 were significantly reduced,while CLZ/r was significantly increased.Conclusions Un-der hypoxic environments,the expression of P-gp in rat liver tissue is significantly downregulated,leading to increased systemic exposure of phenytoin,reduced clearance,and consequently elevated blood concentra-tions,raising the risk of central nervous system toxici-ty.In contrast,SAHA suppresses HDAC5 expression,thereby activating P-gp transcription and enhancing its efflux function.This results in decreased systemic ex-posure and improved clearance of phenytoin,signifi-cantly reducing drug accumulation in body and ulti-mately lowering the risk of adverse effects.
