The Pharmacokinetic Study Of26-OH-panaxadiol

The pharmacokinetic of26-OH-Panaxadiol with anticancer activity in rats wasinitially studied in this paper. Quantitative analysis methods were developed for thedetection of26-OH-Panaxadiol in biological samples. The qualitative analysis assaywas developed for the detection of the metabolites. The absorption, distribution,metabolism, excretion of26-OH-Panaxadiol was clarified, which can elucidate theefficacy and safety of26-OH-Panaxadiol.The results can provide a theory basisfor the further development of26-OH-Panaxadiol into an innovative cancer drugs.1、Plasma concentration-time profile study of26-OH-PanaxadiolA quantitative analysis method based on ultra-performance liquid chromatog-raphy coupled with tandem mass spectrometry(UPLC-MS/MS) was developedfor the detection of26-OH-Panaxadiol in rat plasma. Plasma concentration of26-OH-Panaxadiol was detected after three different oral doses.The results wereas follows:In the low dose,Cmaxwas2803.56±554.51μg/L,AUC(0-t)was23289.06±4091.39μg·h/L.In the middle dose,Cmaxwas6765.06±854.51μg/L,AUC(0-t)was62798.41±16085.25μg·h/L. In the high dose, Cmaxwas11147.59±1568.25μg/L,AUC(0-t)was95560.21±20914.89μg·h/L.The Tmax, V, T1/2and CL were2.8-3.1h,4.20-6.83L/kg,5.5-6.4h and0.5-0.66L/h/kg respectively.The AUC and Cmaxwere proportional to the dose, Tmax, V, T1/2and CL had no obvious difference,which displayed the first order kinetic process.The pharmacokinetic parameters aftera single15.0mg/kg intravenous dose to rats were evaluated.The bioavailabilityof26-OH-Panaxadiol was24.9%.2、Tissue distribution study of26-OH-PanaxadiolA quantitative analysis method based on UPLC-MS/MS was developed for thedetection of26-OH-Panaxadiol in rat tissues. The concentration of26-OH-Panaxadiolat1h,3h,10h and24h were detected in heart, liver, spleen, lung, kidney, stomach,intestine, uterus, testicle, muscle, fat and brain after a single dose of30.0mg/kg. The results were as follows:26-OH-Panaxadiol can extensively and quickly distribute tothe most of the tissues examined, and the concentration was significantly lower thanthe plasma. The highest level was observed in stomach and intestine, and had nolong-term accumulation in all the tissues.3、Plasma protein binding of26-OH-PanaxadiolUPLC-MS/MS methods were established for the content determination of26-OH-Panaxadiol in dog plasma, human plasma and dialysate. Equilibrium dialysismethod was used to determine the protein binding rates of three different kinds ofplasma. The results were as follows: The protein binding rates of rat plasma, dogplasma and human plasma were76%-79%,66%-69%and81%-86%, respectively.There is no concentration-dependent in three different kinds of plasma.4、Excretion study of26-OH-PanaxadiolA quantitative analysis method based on UPLC-MS/MS was developed for thedetection of26-OH-Panaxadiol in rat feces, urine and bile. The concentration of26-OH-Panaxadiol in feces, urine and bile were detected after a single dose of30.0mg/kg. The results were as follows: The maximum excretion rate of26-OH-Panaxadiol in feces and urine was between8h and12h. And the bile wasbetween6h and8h. The percentage of cumulative amount of26-OH-Panaxadiol overa96h period in feces and urine were61.27%,1.62%,respectively. And the cumulativeexcretion rate over a36h period in bile was0.07%. It followed that feces was theprimary excrete route in rats.5、Metabolism study of26-OH-PanaxadiolThe qualitative analysis assay based on ultra-performance liquid chromatographycoupled with Q-Tof spectrometry (UPLC-Q-Tof MS) was developed for the detectionof the metabolites. The metabolites of26-OH-Panaxadiol over a96h period in fecesand urine were preliminary detected after a single dose of30.0mg/kg. The resultswere as follows: Five metabolites were identified in feces, and four metabolites wereidentified in urine. The products were derived from oxidization and dehydration.Theresult suggested that phase Ⅰ metabolic was the main metabolic pathway of26-OH-Panaxadiol in rats.