Pharmacokinetics Studies On Coumarins Choleretic Drug Armillarisin A

Armillarisin A is a new coumarins choleretic drug which acts by facilitating biliation, lessening dodecadactylon tensity and adjusting biliary system pressure. There is a growing interest in the research and development of Armillarisin A due to its excellent performance in the treatment of various disease including hepatitis, cholestasis caused by hepatic cirrhosis, hepatic cirrhosis hyperbilirubinemia, acute pancreatitis, icteric hepatitis, acute cholecystitis and acute cholestatic hepatitis. However, these research were mainly focused on the pharmacological activity, little was known about its Pharmacokinetics, and to our knowledge, no report was available on its Pharmacokinetics research in human.In this paper, A rapid, highly sensitive and accurate LC/MS/MS method was developed and fully validated for the determination of Armillarisin A and its metabolites in human and rats. Based on this robust method, the pharmacokinetics of Armillarisin A in human and rat was investigated. These experiments were useful for the further development of Armillarisin A and can be referred in its clinical application.1. The development of LC/MS/MS method for the determination of Armillarisin A in biological samplesThe optimized chromatography and mass condition for the determination of Armillarisin A in different biological samples were obtained after a serial experiments, and finally a rapid, highly sensitive, accurate LC/MS/MS method was developed and fully validated.The evaluation results of hundreds of biological samples proved that this method was sensitive and fast enough to qualify its application in the pharmacokinetics study.2. Studies on pharmacokinetics of Armillarisin A in rats. The pharmacokinetics of Armillarisin A in rats was investigated by the LC/MS/MS method. Compared to the reported radiolabelled method, this novel one performed better in sensitivity, specificity as well as time-saving(giving a total run time of only 3 min each sample).1.44 mg and 0.9 mg Armillarisin A were given via ig and iv to SD rats, respectively. After iv Armillarisin A, the major pharmacokinetic parameters Tmax, T1/2, AUC(0 -∞) were 0.0833 h, (0.75±0.35)h, (140.64±19.73) mg·/L·h, respectively; After ig Armillarisin A, the main pharmacokinetic parameters Tmax, T1/2, AUC(0 -∞) were 0.333 h,(1.55±0.43)h, (41.87±7.54)mg·/L·h, respectively. The absolute bioavailability was 29.77% after correction of dosage.The results indicated that the absorption, distribution and excretion of Armillarisin A in rats was quite fast, but the oral bioavailability of Armillarisin A was rather low. The reason may be that it may suffer from first–pass metabolism to produce conjugated metabolites.3. Studies on metabolism of Armillarisin A in ratsAfter ig 40 mg/kg Armillarisin A, the urine, bile and excrements were collected at different time. the main metabolites was identified and quantitated by LC/MSn technique. By the analysis of urine samples, the prototype and a de-acetyl metabolites was identified.4. Studies on pharmacokinetics of Armillarisin A in humanTwenty healthy male volunteers took 320 mg Armillarisin A tablet in a single dosing open label, randomized, two-way cross over study. The plasma were collected at different time after administration and the plasma concentration of Armillarisin A were determined by LC/MS/MS method. Based on the acquired data, the concentration time curves were plotted, the main pharmacokinetic parameters were calculated and the relative bioavailability of the test was also evaluated.After a single oral dose administration of the test and the reference, Tmax was 0.35±0.09 and 0.36±0.08 h, respectively; Cmax was 32.94±11.52 and 31.15±8.23 ng/mL, respectively; AUC0-t was 12.92±3.91 and 12.80±4.03 ng?h/mL; respectively,AUC0-∞was 13.10±3.93 and 12.95±4.07 ng?h/mL;Calculated based on AUC0-t,the relative bioavailability of the test was 102.00±16.19%.The analysis of variance on main pharmacokinetic parameters such as Cmax and AUC indicated that there was no significant difference between the two formulations. All the 90% confidence intervals of the test/reference geometric mean ratio of parameters were within the bioequivalence limits. Pharmacokinetic profiles of the two formulations showed that the two products were bioequivalent.5. conclusionIn the present study, a LC/MS/MS method characterized by high-throughput, high sensitivity and specificity was founded and fully validated for the determination of Armillarisin A and its metabolites. The foundation of this LC/MS/MS method is of great reference value for in vivo analysis of Coumarins compounds.The study on pharmacokinetics of Armillarisin A in human and rats was performed by LC/MS/MS method, and the metabolism and excretion of Armillarisin A in rats were also evaluated. These knowledge may be useful for the further development of Armillarisin A.