The Pharmacokinetic Study Of PDD1Guttate Pills

The pharmacokinetic of PPD1guttate pills with antiarrhythmic activity in rat wasinitially studied in this paper. Quantitative analysis methods were developed for thedetection of PPD1in biological samples after oral administration of PPD1guttate pills.The qualitative analysis assay was developed for the detection of the metabolites. Theabsorption， distribution， metabolism and excretion of PPD1in rat body wasclarified， which can elucidate the efficacy， safety and the action principle ofPPD1guttate pills. The results of the study can provide a theory basis for the furtherdevelopment of PPD1guttate pills into an innovative antiarrhythmic drugs.1. Pharmacokinetic study of PPD1guttate pillsA quantitative analysis method based on ultra-performance liquid chromatographycoupled with tandem mass spectrometry (UPLC-MS/MS) was developed for the detectionof PPD1in rat plasma. Plasma cocerntration of PPD1was detected after three differentoral doses of PPD1guttate pills(15.0，30.0，60.0mg/kg amount to PPD1）. The resultswere as follows： In the low dose， Tmax3.17±0.68h，T1/25.65±0.77h，AUC(0-t)26336.44±5077.15μg·h/L，AUC(0-∞)26411.52±5090.26μg·h/L；In the middle dose，Tmax2.92±0.59h，T1/25.78±0.82h，AUC(0-t)52509.77±12223.09μg·h/L，AUC(0-∞)52634.03±12227.01μg·h/L；In the high dose，Tmax3.00±0.78h，T1/252634.03±12227.01h，AUC(0-t)134561.97±23178.93μg·h/L，AUC(0-∞)135086.08±23217.00μg·h/L。In the three different oral doses，the Tmax， T1/2，V and CL haveno obvious difference. AUC and Cmax were proportional to the dose，which displayedthe first order kinetic process. The bioavailability of PPD1guttate pills was62.13%.2. Tissue distribution study of PDD1guttate pillsA quantitative analysis method based on UPLC-MS/MS was developed for thedetection of PDD1in rat tissues. The concerntration of PDD1at1.5h，3h，9and24h were detected in heart，liver，spleen，lung，kidney，stomach，large intestine，smallintestine，uterus，testicle，muscle，fat and brain after a single dose of PDD1guttatepills（30.0mg/kg amount to PDD1）. The results were as follows： PDD1guttate pillscan extensively and quickly distribute to the most of the tissues examined，and theconcerntration was significantly lower than the plasma. The highest level wasobserved in stomach and intestine，and had no long-term accumulation in all thetissues.3. Plasma protein binding of PDD1UPLC-MS/MS methods were established for the concerntration determination ofPDD1in dog plasma， human plasma and dialysate. Equilibrium dialysis method wasused to determine the protein binding rates of three different kinds of plasma（ratplasma，dog plasma， human plasma. The results were as follows：There is noconcerntration-dependent in three different kinds of plasma. The mean protein bindingrates of different concerntration in rat plasma were76.98%，77.58%，77.57%； Indog plasma were76.98%，77.58%，77.57%；And in human plasma were77.59%，78.58%，78.82%. The result suggested that PDD1was a drug combined with highplasma protein.4. Excretion study of PDD1guttate pillsA quantitative analysis method based on UPLC-MS/MS was developed for thedetection of PDD1in rat feces，urine and bile. The concerntration of PDD1in feces，urine and bile were detected after a single dose of PDD1guttate pills (30.0mg/kgamount to PDD1）. The results were as follows： The maximum excretion rate ofPDD1in feces and urine was between8h and12h. And the bile was between6h and8h. The percentage of cumulative amount of PDD1over a96h period in feces andurine were55.39%，0.11%；The cumulative excretion rate over a36h period in bilewas0.016%. It suggested that feces was the primary excrete route in rat.5. Metabolism study of PDD1guttate pillsThe qualitative analysis assay based on ultra-performance liquid chromatography coupled with Q-TOF spectrometry (UPLC-Q-TOF/MS) was developed for thedetection of the metabolites. The metabolites of PDD1over a96h period in feces andurine were preliminary detected after a single dose of PDD1guttate pills（30.0mg/kgamount to PDD1）. The results were as follows：Eleven metabolites were identified infeces， and five metabolites were identified in urine. The result suggested that phaseⅠmetabolic was the main metabolic pathway of PDD1in rat. The products werederived from oxidization and dehydration，separately.