Yan-Fang Yang1, You-Bo Zhang2, Zhi-Jing Chen1, Ying-Tao Zhang3, Xiu-Wei Yang4. 1. State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. 2. State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States. 3. State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: zytao@bjmu.edu.cn. 4. State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: xwyang@bjmu.edu.cn.
Abstract
BACKGROUND: The fruit of Psoralea corylifolia L., Psoraleae fructus (PF), is widely used in traditional Chinese medicine as a well-known herbal tonic. Previous studies have shown that PF and its major constituents may have potential values in the treatment of Parkinson and Alzheimer diseases, though their pharmacokinetics and brain distribution were largely unknown. PURPOSE: To develop a liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for simultaneous studies of the plasma pharmacokinetics and cerebral nuclei (including cerebellum, thalamus, brainstem, hippocampus, corpus striatum and cortex) distribution in rats of eleven known PF compounds following as psoralen, isopsoralen, psoralidin, bavachin, bavachinin, isobavachin, isobavachalcone, bavachalcone, neobavaisoflavone, corylifol A, and corylin. METHODS: Rats were orally administered via gavage at a single dose of PF extract at 1.2 g/kg. The eleven known PF compounds were extracted from rat plasma and cerebral nuclei at different time points, and then determined by the established LC-MS/MS method. Non-compartmental pharmacokinetic profiles were calculated, and the distribution in rat plasma and cerebral nuclei were compared. RESULTS: The results showed that all the tested compounds were quickly absorbed into rat plasma and distributed almost evenly to the cerebral nuclei. The distribution concentrations at different nuclei varied at one determined time point, but the overall trends were basically similar to the plasma concentration-time results. Psoralen and isopsoralen, the two highest coumarins contained in PF, displayed far higher plasma concentrations (AUC0→∞, plasma≈53,884∼65,578 ng·h/ml) and central nervous system penetration (AUC0→∞, brain nuclei ≈44,659∼65,823 ng·h/g) than the prenylflavonoids (other compounds except psoralidin, AUC0→∞, plasma≈69∼324 ng·h/ml; AUC0→∞, brain nuclei ≈119∼3662 ng·h/g). However, the total brain-to-plasma ratios of the prenylflavonoids were higher than the coumarins, suggesting the prenylflavonoids can more readily enter the brain than the coumarins. CONCLUSION: The established LC-MS/MS method is sensitive and specific for the simultaneous quantitation of the eleven PF compounds in rat plasma and cerebral nuclei. The results of plasma pharmacokinetics and cerebral nuclei distribution may reveal the possible substance basis for the CNS activities of PF, and highlight the application possibility of PF and its major constituents in the treatment of Parkinson and Alzheimer diseases.
BACKGROUND: The fruit of Psoralea corylifolia L., Psoraleae fructus (PF), is widely used in traditional Chinese medicine as a well-known herbal tonic. Previous studies have shown that PF and its major constituents may have potential values in the treatment of Parkinson and Alzheimer diseases, though their pharmacokinetics and brain distribution were largely unknown. PURPOSE: To develop a liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for simultaneous studies of the plasma pharmacokinetics and cerebral nuclei (including cerebellum, thalamus, brainstem, hippocampus, corpus striatum and cortex) distribution in rats of eleven known PF compounds following as psoralen, isopsoralen, psoralidin, bavachin, bavachinin, isobavachin, isobavachalcone, bavachalcone, neobavaisoflavone, corylifol A, and corylin. METHODS:Rats were orally administered via gavage at a single dose of PF extract at 1.2 g/kg. The eleven known PF compounds were extracted from rat plasma and cerebral nuclei at different time points, and then determined by the established LC-MS/MS method. Non-compartmental pharmacokinetic profiles were calculated, and the distribution in rat plasma and cerebral nuclei were compared. RESULTS: The results showed that all the tested compounds were quickly absorbed into rat plasma and distributed almost evenly to the cerebral nuclei. The distribution concentrations at different nuclei varied at one determined time point, but the overall trends were basically similar to the plasma concentration-time results. Psoralen and isopsoralen, the two highest coumarins contained in PF, displayed far higher plasma concentrations (AUC0→∞, plasma≈53,884∼65,578 ng·h/ml) and central nervous system penetration (AUC0→∞, brain nuclei ≈44,659∼65,823 ng·h/g) than the prenylflavonoids (other compounds except psoralidin, AUC0→∞, plasma≈69∼324 ng·h/ml; AUC0→∞, brain nuclei ≈119∼3662 ng·h/g). However, the total brain-to-plasma ratios of the prenylflavonoids were higher than the coumarins, suggesting the prenylflavonoids can more readily enter the brain than the coumarins. CONCLUSION: The established LC-MS/MS method is sensitive and specific for the simultaneous quantitation of the eleven PF compounds in rat plasma and cerebral nuclei. The results of plasma pharmacokinetics and cerebral nuclei distribution may reveal the possible substance basis for the CNS activities of PF, and highlight the application possibility of PF and its major constituents in the treatment of Parkinson and Alzheimer diseases.