Pharmacokinetic Study Of Octahydro-9-phenylacetamido Acridine

PurposeOctahydro-9-phenylacetamido acridine is a relatively new compound that has an antiarrhythmic effect.It is the analogue of 9-amino-1,2,3,4,5,6,7,8,-octahydro acridine,and is different in structure from other antiarrhythmic drugs.We do the research in order to develop the efficiency and reduce toxicity at the same time.There are few studies on octahydro-9-phenylacetamido acridine.This article studied its pharmacokinetics,established a quantification method of octahydro-9-phenylacetamido acridine by LC-MS/MS to explore its pharmacokinetic behavior in rats,looked for possible metabolites of octahydro-9-phenylacetamido acridine and speculated its metabolic pathways based on the research.Then,we explored the mechanism deeply,which can provide theoretical basis for clinical application and development of new drug.ProgramThis paper established a reliable LC-MS/MS analysis method,and then verified its feasibility.Plasma samples were prepared by liquid-liquid extraction,and 20 ?L prepared sample was injected for analysis.0.1% formic acid-water solution was used as the solvent A and methanol was used as the solvent B.SB-C18(5 ?m,4.6×150 mm,Agilent,USA)column was selected for analysis.Samples are separated by an isocratic chromatography method with 60% B phase,.Mass spectrometry method: electrospray ionization source(ESI),multiple reaction monitoring(MRM),positive ion detection mode.The ion pairs are m/z 321.3/203.1(octahydro-9-phenylacetamido acridine)and m/z 264.3/58.2(tramadol).The concentration range is 2-300 ng/m L.The residue,selectivity,accuracy and precision,matrix effect,extraction recovery,dilution reliability,and storage stability under various conditions were investigated.The results proved that this method is suitable for studies of rat plasma pharmacokinetics.This study investigated the pharmacokinetics of octahydro-9-phenylacetamido acridine from the following four aspects: 1)determination of blood drug concentration after oral and intravenous adminiatration;2)plasma protein binding rate;3)cumulative excretion of prototype drugs in rat urine and feces;4)characterization of the metabolites in urine samples of octahydro-9-phenylacetamido acridine and metabolic process in rats.ResultThe LC-MS/MS method established in this paper was fully validated.The method is accurate,reliable,reproducible,specific.Extraction recovery was high,and almost no matrix effect were found.The method can meet the relevant requirements of CFDA and be applied to the pharmacokinetics of octahydro-9-phenylacetamido acridine.After giving drugs to rats by gavage and intravenous administration,the elimination half-life was 2.59 ± 1.31 h.and 0.200 ± 0.0200 h.AUC was 2398±1036 ng·h/mL and 582±119 ng·h/m L,respectively.Absolute bioavailability was 8.2%;The plasma protein binding rate of different concentrations of octahydro-9-phenylacetamido acridine was 40%-50%;Octahydro-9-phenylacetamidoacridine was not excluded from the urine,and about 24.1% of the drug was eliminated from the feces.Five metabolites of phase I were found in rats.