Preclinical Pharmacokinetic Study Of Albiflorin

Albiflorin is extracted from Paeonialacti flora Pall and Paeonia veitchii Lynch, belonging to the monoterpene compounds. The pharmacological studies indicated that albiflorin has analgesic, sedative, anticonvulsant effects and the effect of the immune system, anti-inflammatory effect on the role of smooth muscle, anti-pathogenic microorganism and hepatoprotective effect and so on. The latest research shows that albiflorin has antidepressant effects. It can promote sleep, protecting nerve of brain, its pharmacological activity even be stronger than the main component paeoniflorin in Radix Paeoniae Alba. Therefore, the compound has a good development prospects. We plan to make albiflorin into State Category I new drug. The aim of this study is to make a study and evaluation of albiflorin preclinical pharmacokinetics, provide the preliminary basis for clinical study and pharmaceutic preparation study.Objectives:To study pharmacokinetics characteristics of albiflorin, obtain its absorption, distribution, excretion and metabolism data.Methods:Using of LC-MS/MS technology to detect albiflorin in biological samples, and analyz its drug concentration in blood, tissue and excrement. The pharmacokinetic parameters obtained after detection and calculation. Using of in vitro liver microsomes incubation techniques to determine whether albiflorin is metabolized by cytochrome P450 isoforms metabolism, and whether it has inhibition or induction effect on cytochrome P450 isoforms. Use Caco-2 cell model technology, to study absorption characteristics of albiflorin.Results:Established a high sensitivity, strong specificity, simple, rapid analysis method of albiflorin in ICR mice and beagles biological sample. Use LC-MS/MS technology, protein precipitation, to detect the biological samples. Biological matrix does not interfere in the determination of albiflorin. After verification methodology, albiflorin in 1～1000 ng/mL has a good linear range and minimum lower limit of quantification was 1 ng/mL; the method of the inter day and intra day precision (RSD) of less than 12%, accuracy of the method is between 93-107%, the recovery rate is above 85%.After a single oral dose of albiflorin (3.5 mg/kg,7 mg/kg,14 mg/kg) in mice, albiflorin was quickly absorbed and eliminated. It was completely eliminated at 10 h, and three groups" Cmax, AUC were linearly related with doses, which conformed to the first-order elimination kinetics.ICR mice were killed at the time of 10 min,1 h,6 h after a single oral dose of albiflorin 7 mg/kg. The results showed that albiflorin was detected in all tissues at 10 min in a low level. After 1 h drug concentration in all tissues reached the peak. At 6 h albiflorin in tissues was in a low level, which suggested that albiflorin did not have drug accumulation.Pharmacokinetic parameters were measured after a single oral dose of albiflorin (0.5 mg/kg,1 mg/kg,2 mg/kg) in beagles. The result shows that albiflorin was quickly absorbed and eliminated. It was completely eliminated at 10 h, and three groups, Cmax, AUC were linearly related with doses, which conformed to the first-order elimination kinetics.Using in vitro incubation technique, add albiflorin into cytochrome P450 or primary cultured hepatocytes system. The result shows that albiflorin has no induction and inhibition of P450 enzyme isoforms and human primary hepatocytes.Use Caco-2 cell to study the mechanism of absorption of albiflorin. The result shows that albiflorin has poor absorption in Caco-2 cell, efflux rate>2.Conclusion:Albiflorin absorbed and eliminated quickly in ICR mice and beagles, which had a poor absorption, low bioavailability. We found no accumulation in vivo and no induction and inhibition in P450 enzyme isoforms and human primary hepatocytes.