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

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.

Saikosaponin a promotes sleep by decreasing neuronal activities in the lateral hypothalamus

“…Our present study first found that SSa could promote Statistical comparisons were conducted using one-way analysis of variance (ANOVA) followed by protected least significant difference (PLSD) tests. Data represented as mean ± SEM (n = 6), *p < 0.05, **p < 0.01, n.s., no significant difference between two groups rat is 17.5 min (Kwon et al, 2018). Considering that SSa is watersoluble, which means that SSa is comparably hard to penetrate the blood-brain barrier, and the LH is located deep in the brain, the extended time to taking effect might be partly contributed to by the time spent on drug transmission to the target.…”

“…In our present study, it is surprising to find that SSa does not have any effect during the first hour after injection. Based on previous studies, the time taken to reach the maximum concentration (T max ) of 2.3 mg/kg SSa after oral administration in the Sprague‐Dawley rat is 17.5 min (Kwon et al, 2018). Considering that SSa is water‐soluble, which means that SSa is comparably hard to penetrate the blood–brain barrier, and the LH is located deep in the brain, the extended time to taking effect might be partly contributed to by the time spent on drug transmission to the target.…”

Potential Assessment of UGT2B17 Inhibition by Salicylic Acid in Human Supersomes In Vitro

“…The tubes were incubated for 60 min in a water bath at 37 • C. Phenacetin (50 µM, 300 µL) dissolved in ice-cold HPLC-grade acetonitrile was added to each incubation tube for reaction termination. Protein separation was obtained in each incubation tube after centrifuging at 13,000× g for 5 min using a micro centrifuge [16]. Finally, 500 µL of supernatant was collected from each tube and mixed with 300 µL of mobile phase in HPLC vials.…”

<p>Primary Studies on Construction and Evaluation of Ion-Sensitive in situ Gel Loaded with Paeonol-Solid Lipid Nanoparticles for Intranasal Drug Delivery</p>

“…The metabolic type of PAE in the liver was mainly Phase I metabolism, and the main metabolites were 2, 4-dihydroxyacetophenone and four kinds of oxidative metabolites. 26 Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is an indispensable auxiliary factor in the biotransformation of many compounds, which is involved in the reaction of CYP450 enzymes, FMOs enzymes and other oxidases in liver microsomes. 27 The metabolic mechanisms of PAE in different simulated biological samples are shown in Table 2.…”