Pharmacokinetics and Brain Distribution of the Active Components of DA-9805, Saikosaponin A, Paeonol, and Imperatorin in Rats.

Mi Kwon,Hee Kang,Young Cho,Jayoung Ryu,Jin Jeong

doi:10.3390/pharmaceutics10030133

Abstract

DA-9805 is a botanical anti-Parkinson’s drug candidate formulated from ethanol extracts of the root of Bupleurum falcatum, the root cortex of Paeonia suffruticosa, and the root of Angelica dahurica. The pharmacokinetics (PKs) and brain distribution of active/representative ingredients of DA-9805, Saikosaponin a (SSa; 1.1–4.6 mg/kg), Paeonol (PA; 14.8–59.2 mg/kg), and Imperatorin (IMP; 1.4–11.5 mg/kg) were evaluated following the intravenous or oral administration of each pure component and the equivalent dose of DA-9805 in rats. All three components had greater dose-normalized areas under the plasma concentration-time curve (AUC) and slower clearance with higher doses, following intravenous administration. By contrast, dose-proportional AUC values of SSa, PA, and IMP were observed following the oral administration of each pure component (with the exception of IMP at the highest dose) or DA-9805. Compared to oral administration of each pure compound, DA-9805 administration showed an increase in the AUC of SSa (by 96.1–163%) and PA (by 155–164%), possibly due to inhibition of their metabolism by IMP or other component(s) in DA-9805. A delay in the absorption of PA and IMP was observed when they were administered as DA-9805. All three components of DA-9805 showed greater binding values in brain homogenates than in plasma, possibly explaining why the brain-to-plasma ratios were greater than unity following multiple oral administrations of DA-9805. By contrast, their levels in cerebrospinal fluid were negligible. Our results further our understanding of the comprehensive PK characteristics of SSa, PA, and IMP in rats and the comparative PKs between each pure component and DA-9805.

Highlights

The potential role of herbal products in the treatment of Parkinson’s disease has emerged [1]
The dose-normalized areas under the plasma concentration-time curve (AUC) values of Saikosaponin a (SSa), PA, and IMP following intravenous administration tended to increase with dose elevation because of slower CL ( CLNR ) of the drugs in the higher dose group(s)
A significantly smaller volume of distribution at steady state (V ss), longer mean residence time (MRT), and smaller Ae0–24h of SSa were observed in the higher dose group

Summary

Introduction

The potential role of herbal products in the treatment of Parkinson’s disease has emerged [1]. Neuroprotective or neurorestorative agents for the treatment of this disease by either inhibiting primary neurodegenerative events or boosting compensatory and regenerative mechanisms in the brain remain an unmet medical need [2]. DA-9805, a novel botanical neuroprotective anti-Parkinson’s drug candidate, was formulated from ethanol extracts of the mixture (1:1:1, w/w/w) of three herbal drugs, the root of Bupleurum falcatum L. An investigational new drug application for DA-9805 for a phase II clinical study was recently submitted to the U.S Food and Drug Administration. The neuroprotective effects of each of the three herbal constituents in DA-9805 have been reported in various in vitro and animal models. Ethanol extracts of the root of B. falcatum have been shown to inhibit neuroinflammation in murine microglial

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Conclusion