Corydaline Inhibits Multiple Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

Hye Young Ji,Hyeri Lee,Hyun Joo Shim,Kwang Hyeon Liu,Sae Rom Im,Miwon Son,Hye Suk Lee

doi:10.3390/molecules16086591

Abstract

Corydaline is a bioactive alkaloid with various antiacetylcholinesterase, antiallergic, and antinociceptive activities found in the medicinal herb Corydalis Tubers. 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 Ki values of 1.7 and 7.0 μM, respectively. Corydaline also demonstrated moderate inhibition of UGT1A1-mediated 17β-estradiol 3-glucuronidation and UGT1A9-mediated propofol glucuronidation with Ki values of 57.6 and 37.3 μM, respectively. In the presence of corydaline, CYP3A-mediated midazolam hydroxylation showed a decrease with increasing preincubation time in a dose-dependent manner with Ki values of 30.0 μM. 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.

Highlights

Corydalis tubers, the roots of Corydalis yanhusuo W.T
The inhibitory potencies of corydaline were not significantly affected after a 30-min period of pre-incubation with human liver microsomes in the presence of NADPH, excluding CYP3A activity (Table 1), indicating that corydaline is a mechanism based inhibitor of CYP3A
To determine whether midazolam metabolism is inhibited by corydaline, we performed time- and concentration-dependent inactivation assays in human liver microsomes

Summary

Introduction

The roots of Corydalis yanhusuo W.T. Wang, have long been used as an herbal drug for their analgesic and anti-ulcer effects [1,2,3]. Because botanical drugs share the same metabolic and transport proteins, including cytochrome P450 (CYP) enzymes, UDP-glucuronosyltransferase (UGT) enzymes, and drug transporters, such as P-glycoprotein, with commonly used drugs, the potential for herb-drug interactions is substantial [11]. Modulation of drug-metabolizing enzymes, such as CYP and UGT enzymes, is one of the important mechanisms of drug interaction. To the best of our knowledge, no previous study has reported on the effect of corydaline, a pharmacologically active isoquinoline alkaloid isolated from Corydalis tubers, on human CYP and UGT enzymes. The effects of corydaline on activities of seven major human CYP and four major human UGTs (1A1, 1A4, 1A9, and 2B7), were examined using pooled human liver microsomes in order to evaluate the possibility of corydaline-drug interactions

Results and Discussion

Materials and Reagents

Kinetic Analysis

Data Analysis

Conclusions