Corydaline

J Sep Sci. 2012 May;35(9):1102-9.

In vitro metabolism of corydaline in human liver microsomes and hepatocytes using liquid chromatography-ion trap mass spectrometry.[Pubmed: 22689485]

Corydaline is a pharmacologically active isoquinoline alkaloid isolated from Corydalis tubers. It exhibits the antiacetylcholinesterase, antiallergic, antinociceptive, and gastric emptying activities. The purposes of this study were to establish in vitro metabolic pathways of Corydaline in human liver microsomes and hepatocytes by identification of their metabolites using liquid chromatography-ion trap mass spectrometry.
METHODS AND RESULTS:
Human liver microsomal incubation of Corydaline in the presence of an NADPH-generating system resulted in the formation of nine metabolites, namely, four O-desmethylCorydaline [M1 (yuanhunine), M2 (9-O-desmethylCorydaline), M3 (isocorybulbine), and M4 (corybulbine)], three di-O-desmethylCorydaline [M5 (9,10-di-O-desmethylCorydaline), M6 (2,10-di-O-desmethylCorydaline), and M7 (3,10-di-O-desmethylCorydaline)], M8 (hydroxyyuanhunine), and M9 (hydroxyCorydaline). Incubation of Corydaline in human hepatocytes produced four metabolites including M1, M5, M6, and M9.
CONCLUSIONS:
O-Demethylation and hydroxylation were the major metabolic pathways for the metabolism of Corydaline in human liver microsomes and hepatocytes.

J Asian Nat Prod Res . 2017 Nov;19(11):1124-1133.

Corydaline inhibits enterovirus 71 replication by regulating COX-2 expression[Pubmed: 29034730]

Abstract Enterovirus 71 (EV71) is a huge threat to the worldwide public health and there is no approved antiviral drug for EV71-induced disease therapy. Corydaline exists antiallergic and antinociceptive activities, but the anti-EV71 activity of Corydaline is still not reported. In this study, Corydaline could suppress the expression of viral structural and non-structural proteins. Furthermore, Corydaline inhibits EV71 replication by suppressing the COX-2 expression and the phosphorylation of JNK MAPK and P38 MAPK but not ERK MAPK in vitro. Based on these findings, Corydaline could be a potential lead or supplement for the development of new anti-EV71 agents in the future. Keywords: COX-2; Corydaline; MAPK; enterovirus 71.

Xenobiotica. 2014 Nov 28:1-8.

Gender differences in corydaline pharmacokinetics in rats.[Pubmed: 25430796]

1. Corydaline, an isoquinoline alkaloid, is one of the major active constituents in a new prokinetic botanical agent, DA-9701. It has been recommended that preclinical pharmacokinetic studies of natural medicines include both genders. Therefore, in this study, the pharmacokinetics of Corydaline in male and female rats was evaluated following intravenous and oral administration of pure Corydaline or DA-9701.
METHODS AND RESULTS:
2. After intravenous administration of Corydaline, the area under the plasma concentration-time curve (AUC) was significantly greater (by 46.4%) in female rats compared to male rats due to a 29.3% reduction in non-renal clearance in female rats. The gender difference in Corydaline hepatic metabolic clearance was supported by a significantly slower metabolism of Corydaline in hepatic microsomes of female rats mediated via male-specific (CYP2C11 and CYP3A2) or male-dominant (CYP3A1) CYP isozymes. 3. Following oral administration of pure Corydaline or DA-9701, the AUC and Cmax values of Corydaline in female rats were significantly greater (by 793% and 466% increase for Corydaline administration or by 501% and 143% increase for DA-9701 administration) than in male rats. Greater F values of Corydaline in female rats could be due to smaller hepatic first-pass extraction as a result of slower hepatic metabolism of Corydaline. 4. However, we observed a comparable disappearance of Corydaline in male and female human liver microsomes, consistent with little gender difference in CYP2C9 and CYP3A activities in humans compared to that in rats.
CONCLUSIONS:
Thus, gender differences in Corydaline metabolism are not expected to occur in humans.

Biol Pharm Bull. 2010;33(6):958-62.

Effects of corydaline from Corydalis tuber on gastric motor function in an animal model.[Pubmed: 20522959]

The aim of this study was to evaluate the prokinetic and gastric-relaxing effects of the isoquinoline alkaloid Corydaline, which was extracted from Corydalis tubers (CT). Corydaline is a marker compound used for quality control of DA-9701, a prokinetic agent formulated from extracts of Pharbitidis semen and Corydalis tuber that is currently in clinical trials in Korea for the treatment of functional dyspepsia (FD). DA-9701 was previously reported to be a potential therapeutic agent for the treatment of abnormalities in gastrointestinal motor function in FD patients; however, the therapeutic effects of Corydaline on FD have yet to be demonstrated in an in vivo study.
METHODS AND RESULTS:
In the current study, oral administration of Corydaline not only significantly accelerated gastric emptying in normal rats but also improved delayed gastric emptying to near normal levels. Furthermore, Corydaline induced significant gastric relaxation, shifting the pressure-volume curve towards higher volumes compared to controls.
CONCLUSIONS:
These results suggest that Corydaline promotes gastric emptying and small intestinal transit and facilitates gastric accommodation.

Sci Rep . 2020 Aug 14;10(1):13804.

Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists[Pubmed: 32796875]

Abstract Pain remains a key therapeutic area with intensive efforts directed toward finding effective and safer analgesics in light of the ongoing opioid crisis. Amongst the neurotransmitter systems involved in pain perception and modulation, the mu-opioid receptor (MOR), a G protein-coupled receptor, represents one of the most important targets for achieving effective pain relief. Most clinically used opioid analgesics are agonists to the MOR, but they can also cause severe side effects. Medicinal plants represent important sources of new drug candidates, with morphine and its semisynthetic analogues as well-known examples as analgesic drugs. In this study, combining in silico (pharmacophore-based virtual screening and docking) and pharmacological (in vitro binding and functional assays, and behavioral tests) approaches, we report on the discovery of two naturally occurring plant alkaloids, corydine and Corydaline, as new MOR agonists that produce antinociceptive effects in mice after subcutaneous administration via a MOR-dependent mechanism. Furthermore, corydine and Corydaline were identified as G protein-biased agonists to the MOR without inducing β-arrestin2 recruitment upon receptor activation. Thus, these new scaffolds represent valuable starting points for future chemical optimization towards the development of novel opioid analgesics, which may exhibit improved therapeutic profiles.

Molecules. 2011 Aug 5;16(8):6591-602.

Corydaline inhibits multiple cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in human liver microsomes.[Pubmed: 21826053]

Corydaline is a bioactive alkaloid with various antiacetylcholinesterase, antiallergic, and antinociceptive activities found in the medicinal herb Corydalis Tubers.
CONCLUSIONS:
The inhibitory potential of Corydaline on the activities of seven major human cytochrome P450 and four UDP-glucuronosyltransferase enzymes in human liver microsomes was investigated using LC-tandem MS. Corydaline was found to inhibit CYP2C19-catalyzed S-mephenytoin-4'-hydroxylatoin and CYP2C9-catalyzed diclofenac 4-hydroxylation, with K(i) values of 1.7 and 7.0 mM, respectively. Corydaline also demonstrated moderate inhibition of UGT1A1-mediated 17b-estradiol 3-glucuronidation and UGT1A9-mediated propofol glucuronidation with K(i) values of 57.6 and 37.3 mM, respectively. In the presence of Corydaline, CYP3A-mediated midazolam hydroxylation showed a decrease with increasing preincubation time in a dose-dependent manner with K(i) values of 30.0 mM.
CONCLUSIONS:
These in vitro results suggest that Corydaline should be evaluated for potential pharmacokinetic drug interactions in vivo due to potent inhibition of CYP2C19 and CYP2C9.

Xenobiotica. 2014 Jul;44(7):635-43.

Pharmacokinetics of chlorogenic acid and corydaline in DA-9701, a new botanical gastroprokinetic agent, in rats.[Pubmed: 24417753]

1.Few studies describing the pharmacokinetic properties of chlorogenic acid (CA) and Corydaline (CRD) which are marker compounds of a new prokinetic botanical agent, DA-9701, have been reported.
METHODS AND RESULTS:
The aim of the present study is to evaluate the pharmacokinetic properties CA and Corydaline following intravenous and oral administration of pure CA (1-8 mg/kg) or Corydaline (1.1-4.5 mg/kg) and their equivalent dose of DA-9701 to rats. 2.  Dose-proportional AUC and dose-independent clearance (10.3-12.1 ml/min/kg) of CA were observed following its administration. Oral administration of CA as DA-9701 did not influence the oral pharmacokinetic parameters of CA. Incomplete absorption of CA, its decomposition in the gastrointestinal tract, and/or pre-systemic metabolism resulted in extremely low oral bioavailability (F) of CA (0.478-0.899%). 3.  Corydaline showed greater dose-normalized AUC in the higher dose group than that in lower dose group(s) after its administration due to saturation of its metabolism via decreased non-renal clearance (by 51.3%) and first-pass extraction. As a result, the F of Corydaline following 4.5 mg/kg oral Corydaline (21.1%) was considerably greater than those of the lower dose groups (9.10 and 13.8%). However, oral administration of Corydaline as DA-9701 showed linear pharmacokinetics as a result of increased AUC and F in lower-dose groups (by 182% and 78.5%, respectively) compared to those of pure Corydaline.
CONCLUSIONS:
The greater oral AUC of Corydaline for DA-9701 than for pure Corydaline could be due to decreased hepatic and/or GI first-pass extraction of Corydaline by other components in DA-9701.