Studies On Drug Metabolism&Pharmacokinetics Of An Radioprotector VND3207in Rat

VND3207, a vanillin derivative, also known as Syringaldehyde, is a candidatedrug for radioprotection. Previous pharmacodynamic studies have shown that it hasprotective and therapeutic effect of ionizing radiation damage. Therefore, metabolismand pharmacokinetics studies of VND3207are urgent needed.LC-MS based qualitative and quantitative analysis method is a powerful tool fordrug metabolism and pharmacokinetics studies. By using LightSight, a professionaldata analysis software for drug metabolism, based on the characters of VND3207inmass spectrometric analysis and the common reactions of drug biotransformation, aseries of LC-MS acquisition methods were created and applied in a LC-MS system forpreliminary screening of metabolites of VND3207in rat. The results showed that atotal of7metabolites were detected from the biological samples of rat plasma, bile,urine and feces, including3Phase I metabolites （M1、M2、M6） and4Phase IImetabolites （M3、M4、M5、M7）. Metabolic reactions involved are oxidation, reduction,demethylation, sulfate conjugation and glucuronic acid conjugation. Also there weresome of VND3207detected. It may pass out of the body directly via bile and feceswithout biotransformations. So the main metabolic organ of VND3207is liver, andthen the metabolites are excreted via bile.Based on the qualitative pharmacokinetic analysis, a rapid, specific, sensitive,accurate and high throughput LC-MS method was developed for quantitativepharmacokinetic analysis of VND3207in rat plasma. This method could simultaneousdetect VND3207and its main metabolites Syringicacid and Syringic Alcohol, andwith Vanillin as Internal standard, the calibration curves have liner dynamic range of2～2000μg·L^-1and a lower limit of quantification （LLOQ） of2μg·L^-1. According tothe requirements of pharmacokinetics quantitative analysis, the specificity, intra-dayand inter-day precision, matrix effects, recovery and stability of the assay were allvalidated. The pharmacokinetic study results in rat indicated that after p.o.administration of VND3207in the dose range of35～140mg·kg^-1, the metabolismof VND3207and Syringicacid presented typical linear kinetic characters, but SyringicAlcohol possessed a typical non-linear kinetic character. And Syringicacid has largerAUC, longer T_1/2and MRT and higher Cmax than VND3207, so Syringicacid is morelikely to be the potentially active metabolite.The pharmacokinetic studies of VND3207provided the theoretical basis for deepresearch on mechanisms of drug metabolism, interaction between the drug andmetabolizing enzymes, prediction of drug interactions and clinical pharmacokinetic studies.