Pharmacokinetics and Brain Distribution of Tetrahydropalmatine and Tetrahydroberberine after Oral Administration of DA-9701, a New Botanical Gastroprokinetic Agent, in Rats

Abstract

DA-9701 produces strong gastroprokinetic effects at an effective dose of 0.3-3 mg/kg in rats and its safety profile is superior to conventional prokinetics, such as cisapride, mosapride, itopride, and domperidone. 1)HPLC identified chlorogenic acid and corydaline as the major constituents in DA-9701. 5) Chlorogenic acid and corydaline have been selected as marker compounds to ensure consistent concentrations among batches of Pharbitidis semen and Corydalis tuber, respectively, and are known to be the active ingredients in DA-9701. Recently, the pharmacokinetics of chlorogenic acid and corydaline after intravenous and oral administration of pure chlorogenic acid, corydaline, or DA-9701 to rats were reported by our laboratory.6) Linear pharmacokinetics of chlorogenic acid were observed following intravenous (1-4 mg/kg) and oral (1-8 mg/kg) administration of chlorogenic acid or DA-9701. The extent of absolute oral bioavailability (F) of chlorogenic acid was extremely low, 0.478-0.899%, possibly because of incomplete absorption, decomposition in the gastrointestinal (GI) tract, and/or presystemic metabolism. The pharmacokinetics of corydaline were non-linear upon intravenous and oral administration of corydaline (1.1-4.5 mg/kg), possibly because of saturation of corydaline metabolism at higher doses. However, linear pharmacokinetics of corydaline were observed following oral administration of DA-9701. Besides chlorogenic acid and corydaline, DA-9701 contains tetrahydropalmatine (THP), tetrahydroberberine (THB), caffeic acid, coptisine, palmatine, berberine, and dehydrocorydaline (reports from Dong-A Pharmaceutical Co., Ltd.). Among these constituents, we focused on THP and THB (Figs. 1A, B, respectively) because of their dopamine D 2 receptor antagonizing activity (the IC 50 values of THP and THB against GTPγS binding to dopamine D 2S receptor in human recombinant Chinese hamster ovary (CHO) cells are 1.32 µM (469 ng/ mL) and 0.622 µM (211 ng/mL), respectively, according to preliminary reports from Dong-A Pharmaceutical Co., Ltd.). Other major constituents in DA-9701 including corydaline, chlorogenic acid, berberine, and palmatine did not show any activity on dopamine D 2 receptor at concentration ranges of 0.1-10 µM for corydaline and 0.1-1 µM for the others according to the radioligand ([

A Comprehensive Review on the Chemical Properties, Plant Sources, Pharmacological Activities, Pharmacokinetic and Toxicological Characteristics of Tetrahydropalmatine

“…By contrast, CYP inhibitors significantly affect the systemic levels of THP and its metabolites ( Xiao et al, 2021 ). Moreover, the effective oral dose of DA-9701, which is a new botanical gastroprokinetic agent, can decrease the brain concentrations of THP and inhibit THP from exerting central D 2 R antagonism ( Jung et al, 2015 ).…”

The Influence of Palmatine Isolated from Berberis sibirica Radix on Pentylenetetrazole-Induced Seizures in Zebrafish

“…The dataset used here includes 13 structurally similar compounds, which belong to the alkaloids, with reported activity on the CNS. The new established QSAR model combines the experimentally determined logBB values (Table 1) taken from the literature [30][31][32][33][34][35][36][37] with chosen physicochemical descriptors, namely, the hydrogen bond acidity A value, the lipophilic logP o/w value, and the molecular weight (MW) (Table 1). The hydrogen bond acidity values were calculated based on the Linear Free Energy Relationships (LFER) of the Abraham model [38].…”

“…Physicochemical parameters (ACD/Percepta software) and the experimentally obtained logBB values (logBB exp )[30][31][32][33][34][35][36][37]. Analysis of variance obtained for Equation(1).…”

Double‐Blind, Randomized, Placebo‐Controlled Trial of DA‐9701 in Parkinson's Disease: PASS‐GI Study

“…DA‐9701 was developed by a new screening frame of a Korean research and development company searching for an ideal candidate exerting “multiple actions” on GI‐tract 5‐HT 4 , 5‐HT 1, α 2 , and D 2 receptors 5 . Among the metabolites of DA‐9701, tetrahydropalmatine and tetrahydroberberine have D 2 ‐receptor antagonizing activity 56 . However, in animal studies with 50 to 100 times higher doses of DA‐9701 than a therapeutic oral dose (which is a similarly high dose for humans), the maximum concentrations of the 2 constituents in the brain were much lower than the half‐maximal inhibitory concentration values for D 2 ‐receptor antagonism by both of them 56 .…”

“…Among the metabolites of DA‐9701, tetrahydropalmatine and tetrahydroberberine have D 2 ‐receptor antagonizing activity 56 . However, in animal studies with 50 to 100 times higher doses of DA‐9701 than a therapeutic oral dose (which is a similarly high dose for humans), the maximum concentrations of the 2 constituents in the brain were much lower than the half‐maximal inhibitory concentration values for D 2 ‐receptor antagonism by both of them 56 . This means that DA‐9701 with a therapeutic dose hardly has central antidopaminergic activity and it does not significantly induce hyperprolactinemia in humans as consistently reported by several independent studies 5,21,24 .…”