Effect of a New Prokinetic Agent DA-9701 Formulated with Corydalis Tuber and Pharbitidis Semen on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

Hye Young Ji,Hye Suk Lee,Ji Hyeon Jeong,Dae-Young Lee,Miwon Son,Kwang Hyeon Liu,Hyun Joo Shim

doi:10.1155/2012/650718

Abstract

DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP) enzymes and four UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC50) values of 188 and 290 μg/mL, respectively. DA-9701 inhibited CYP2D6-catalyzed bufuralol 1′-hydroxylation with an inhibition constant (K i) value of 6.3 μg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol 1′-hydroxylation, with a K i value of 3.7 μg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC50 equivalent concentration (volume per dose index) value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate the in vivo extent of the observed in vitro interactions.

Highlights

Functional dyspepsia is a very common chronic gastrointestinal disorder, with a prevalence of 40% using the more liberal criteria [1]
CYP2D6-catalyzed bufuralol 1 -hydroxylation activity was inhibited by DA9701 and Corydalis tuber extract with IC50 values of 25.9 and 15.8 μg/mL, respectively, but not by Pharbitidis semen extract (Table 1)
We evaluated the inhibitory potential of DA-9701, Corydalis tuber extract, and Pharbitidis semen extract on four major UGT isoform activities

Summary

Introduction

Functional dyspepsia is a very common chronic gastrointestinal disorder, with a prevalence of 40% using the more liberal criteria [1]. T. Wang and Pharbitidis semen from the seed of Pharbitis nil Choisy, and it is used as an oral therapy (Motilitone ) for the treatment of functional dyspepsia (FD) in Republic of Korea since May 2011 [6,7,8]. To the best of our knowledge, no previous study has reported the effects of Corydalis tubers and Pharbitidis semen, the component herbs of DA-9701, on human CYP and UGT enzymes. The effects of DA-9701 and its component herbs, Corydalis tubers and Pharbitidis semen, on the activities of seven major human CYP enzymes and four major human UGTs, 1A1, 1A4, 1A9, and 2B7, were examined using pooled human liver microsomes in order to evaluate the possibility of drug interactions of DA-9701

Experimental

Results and Discussion

Conclusions