Study on Pharmacokinetics of Metabolites of Adefovir in Rats after Intragastric Administration of Adefovir Derivatives
- VernacularTitle:阿德福韦衍生物灌胃给药后的代谢产物阿德福韦在大鼠体内的药动学研究
- Author:
Tao XIAO
1
,
2
;
Yang YANG
1
,
2
;
Tao LI
1
,
2
;
Jing LI
1
,
2
;
Xiaozhong FU
2
;
Dirong WU
2
;
Yang WANG
2
;
Hong XIAO
2
Author Information
1. Key Lab of Pharmaceutics of Guizhou Provience，Guizhou Medical University，Guiyang 550004，China
2. Engineering Research Center for the Development and Application of Ethnic Medicine and TCM，School of Pharmacy，Guizhou Medical University，Guiyang 550004，China
- Publication Type:Journal Article
- Keywords:
Adefovir;
Adefovir derivative;
HPLC-MS/MS;
Pharmacokinetics
- From:
China Pharmacy
2019;30(9):1173-1177
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE： To establish a method for the determination of adefovir （PMEA） and study the pharmacokinetics of metabolites PMEA in rats after intragastric administration of PMEA derivatives [PMEA prodrug， adefovir-ursodeoxycholic acid-3-propyl ester， L-leucine-3-propyl ester （PMEA-1c）] in rats. METHODS： HPLC-MS/MS method was adopted. The determination was performed on BEH C18 column with mobile phase consisted of 0.1％ formic acid acetonitrile-0.1％ formic acid water （gradient elution） at the flow rate of 0.25 mL/min. The column temperature was 30 ℃， and sample size was 1 μL. The quantitative ions were PMEA m/z 274.1→162.1， puerarin （internal standard） m/z 417.1→267.1. 12 rats were randomly divided into adefovir dipivoxil （ADV） group （positive control， 90 mg/kg） and PMEA-1c group （160 mg/kg）， with 6 rats in each group. They were given relevant medicine once intragstrically， and the blood samples were collected from tail vein 0.083， 0.25， 0.5， 0.75， 1， 2， 4， 6， 8， 10， 12， 24 h after administration to determine the plasma concentration of PMEA. Relevant pharmacokinetic parameters were calculated by using DAS 2.0 software. RESULTS： The linear range of PMEA was 6.1-440.0 ng/mL （r＝0.998 5）. RSDs of intra and inter day of precision and stability tests were all less than 10％ （n＝3， 5， 6）， and the accuracy was 82.16％-97.33％ （RSD≤6.4％， n＝5）. Matrix effects ranged from 95.96％-106.35％ （RSD≤4.9％， n＝5）. The pharmacokinetic parameters of PMEA in ADV group and PMEA-1c group were as follows as t1/2 were （1.762±0.117） and （2.548±0.174） h； AUC0-24 h were （2 170.059±146.091） and （4 704.257±176.792） μg·h/L； cmax were （613.092±9.504） and （697.295±15.275） μg/L， respectively. Compared with ADV group， t1/2， AUC0-24 h， AUC0-∞ and cmax of rats in PMEA-1c group were increased significantly （P＜0.01 or P＜0.001）. CONCLUSIONS： Established method is accurate and reliable. The trial indicates that PMEA-1c metabolism is single compartment model， show that can be used as a potential prodrug for adefovir， which lay a foundation for the further study of adefovir prodrug.
