Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Chinese Medicine
Published in: Chinese Medicine 1/2020

01-12-2020 | Pharmacokinetics | Research

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug–drug interactions

Authors: Zifei Qin, Mengmeng Jia, Jing Yang, Han Xing, Zhao Yin, Zhihong Yao, Xiaojian Zhang, Xinsheng Yao

Published in: Chinese Medicine | Issue 1/2020

Login to get access

Abstract

Background

Kang-Ai injection is widely used as an adjuvant therapy drug for many cancers, leukopenia, and chronic hepatitis B. Circulating alkaloids and saponins are believed to be responsible for therapeutic effects. However, their pharmacokinetics (PK) and excretion in vivo and the risk of drug–drug interactions (DDI) through inhibiting human cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes remain unclear.

Methods

PK and excretion of circulating compounds were investigated in rats using a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC–MS) method. Further, the inhibitory effects of nine major compounds against eleven CYP and UGT isozymes were assayed using well-accepted specific substrate for each enzyme.

Results

After dosing, 9 alkaloids were found with Cmax and t1/2 values of 0.17–422.70 μmol/L and 1.78–4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with t1/2 values of 0.63–7.22 h, whereas other trace saponins could be negligible or undetected. Besides, over 90% of alkaloids were excreted through hepatobiliary and renal excretion. Likewise, astragalosides and protopanaxatriol (PPT) type ginsenosides also involved in hepatobiliary and/or renal excretion. Protopanaxadiol (PPD) type ginsenosides were mainly excreted to urine. Furthermore, PPD-type ginsenosides were extensively bound (fu-plasma approximately 1%), whereas astragalosides and PPT-type ginsenosides displayed fu-plasma values of 12.35% and 60.23–87.36%, respectively. Moreover, matrine, oxymatrine, astragaloside IV, ginsenoside Rg1, ginsenoside Re, ginsenoside Rd, ginsenoside Rc, and ginsenoside Rb1 exhibited no inhibition or weak inhibition against several common CYP and UGT enzymes IC50 values between 8.81 and 92.21 μM. Through kinetic modeling, their inhibition mechanisms towards those CYP and UGT isozymes were explored with obtained Ki values. In vitro-in vivo extrapolation showed the inhibition of systemic clearance for CYP or UGT substrates seemed impossible due to [I]/Ki no more than 0.1.

Conclusions

We summarized the PK behaviors, excretion characteristics and protein binding rates of circulating alkaloids, astragalosides and ginsenosides after intravenous Kang-Ai injection. Furthermore, weak inhibition or no inhibition towards these CYP and UGT activities could not trigger harmful DDI when Kang-Ai injection is co-administered with clinical drugs primarily cleared by these CYP or UGT isozymes.
Appendix
Available only for authorised users
Literature
1.
Ning ZW, Zhai LX, Peng J, Zhao L, Huang T, Lin CY, Chen WH, Luo Z, Xiao HT, Bian ZX. Simultaneous UPLC-TQ-MS/MS determination of six active components in rat plasma: application in the pharmacokinetic study of Cyclocarya paliurus leaves. Chin Med. 2019;14:28.PubMedPubMedCentral
2.
Yao ZH, Qin ZF, He LL, Wang XL, Dai Y, Qin L, Gonzalez FJ, Ye WC, Yao XS. Identification, bioactivity evaluation and pharmacokinetics of multiple components in rat serum after oral administration of Xian-Ling-Gu-Bao capsule by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. J Chromatogr B. 2017;1041–1042:104–12.
3.
4.
Lu T, Yang J, Gao X, Chen P, Du F, Sun Y, Wang F, Xu F, Shang H, Huang Y, Wang Y, Wan R, Liu C, Zhang B, Li C. Plasma and urinary tanshinol from Salvia miltiorrhiza (Danshen) can be used as pharmacokinetic markers for cardiotonic pills, a cardiovascular herbal medicine. Drug Metab Dispos. 2008;36(8):1578–86.PubMed
5.
Cheng C, Du F, Yu K, Xu F, Wang F, Li L, Olaleye OE, Yang J, Chen F, Zhong C, Liu Q, Li J, Wang Z, Li C, Xiao W. Pharmacokinetics and disposition of circulating iridoids and organic acids in rats intravenously receiving ReDuNing injection. Drug Metab Dispos. 2016;44(11):1853–8.PubMed
6.
Lu Q, Li CL. Therapeutic efficacy and safety of Kang-ai injection combined with platinum-based doublet chemotherapy in advanced NSCLC: a meta-analysis. Life Sci. 2018;210:9–19.PubMed
7.
He ZF, Wang JJ, Wang WD. Effect of Kangý ai injection on serum level of soluble interleukin-2 receptor and vascular endothelial growth factor in patients with esophageal carcinoma during radiotherapy. Chin J Integr Med. 2006;12(4):273–6.PubMed
8.
Wan YM, Li YH, Xu ZY, Wu HM, Xu Y, Yang M, Wu XN. The effect of transarterial chemoembolization in combination with kang’ai injection on patients with intermediate stage hepatocellular carcinoma: a prospective study. Integr Cancer Ther. 2018;17(2):477–85.PubMed
9.
Jia M, Zhang B, Qi Y, Yang J, Yao Z, Qin Z, Zhang X, Yao X. Ultra high-performance liquid chromatography coupled with mass spectrometry and chemometric analysis of Kang-Ai injection based on the chemical characterization, simultaneous quantification and relative quantification of forty-seven herbal alkaloids and saponins. J Sep Sci. 2020. https://​doi.​org/​10.​1002/​jssc.​201900878.CrossRefPubMed
10.
Yang J, Dai G, Hou Y, Song Z, Wang F, Ji G, Chen J. Quantification of oxymatrine in rat plasma by UPLC-MS/MS to support the pharmacokinetic analyses of oxymatrine-loaded polymersomes. Anal Methods. 2014;6(6):1811–7.
11.
Wu XL, Hang TJ, Shen JP, Zhang YD. Determination and pharmacokinetic study of oxymatrine and its metabolite matrine in human plasma by liquid chromatography tandem mass spectrometry. J Pharm Biomed Anal. 2006;41(3):918–24.PubMed
12.
Xu M, Yin J, Xie L, Zhang J, Zou C, Zou J, Liu F, Ju W, Li P. Pharmacokinetics and tolerance of toal astragalosides after intravenous infusion of astragalosides injection in healthy Chinese volunteers. Phytomedicine. 2013;20(12):1105–11.PubMed
13.
Jin Y, Guo X, Yuan B, Yu W, Suo H, Li Z, Xu H. Disposition of astragaloside IV via enterohepatic circulation is affected by the activity of the intestinal microbiome. J Agric Food Chem. 2015;63(26):6084–93.PubMed
14.
Zhang WD, Zhang C, Liu RH, Li HL, Zhang JT, Mao C, Moran S, Chen CL. Preclinical pharmacokinetics and tissue distribution of a natural cardioprotective agent astragaloside IV in rats and dogs. Life Sci. 2006;79(8):808–15.PubMed
15.
Ran R, Zhang C, Li R, Chen B, Zhang W, Zhao Z, Fu Z, Du Z, Du X, Yang X, Fang Z. Evaluation and Comparison of the Inhibition Effect of astragaloside IV and aglycone cycloastragenol on various UDP-glucuronosyltransferase (UGT) isoforms. Molecules. 2016;21(12):1616.PubMedCentral
16.
Olaleye OE, Niu W, Du FF, Wang FQ, Xu F, Pintusophon S, Lu JL, Yang JL, Li C. Multiple circulating saponins from intravenous ShenMai inhibit OATP1Bs in vitro: potential joint precipitants of drug interactions. Acta Pharmacol Sin. 2018;40(6):833–49.PubMedPubMedCentral
17.
Yao Z, Li S, Qin Z, Hong X, Dai Y, Wu B, Ye W, Gonzalez FJ, Yao X. Characterization of human UDP-glucuronosyltransferases responsible for glucuronidation and inhibition of norbakuchinic acid, a primary metabolite of hepatotoxicity and nephrotoxicity component bakuchiol in Psoralea corylifolia L. RSC Adv. 2017;7:52661–71.
18.
Gao L, Qin Z, Zhang B, Yin Z, Yang XZJ. An investigation of the metabolic activity, isozyme contribution, species differences and potential drug–drug interactions of PI-103, and the identification of efflux transporters for PI-103-Oglucuronide in HeLa1A9 cells. RSC Adv. 2020;10:9610–22.
19.
Sun ZH, Chen J, Song YQ, Dou TY, Zou LW, Hao DC, Liu HB, Ge GB, Yang L. Inhibition of human carboxylesterases by ginsenosides: structure-activity relationships and inhibitory mechanism. Chin Med. 2019;14:56.PubMedPubMedCentral
20.
Ge G. Deciphering the metabolic fates of herbal constituents and the interactions of herbs with human metabolic system. Chin J Nat Med. 2019;17(11):801–2.PubMed
21.
Lv X, Xia Y, Finel M, Wu J, Ge G, Yang L. Recent progress and challenges in screening and characterization of UGT1A1 inhibitors. Acta Pharm Sin B. 2019;9(2):258–78.PubMed
22.
Zhou QH, Zhu YD, Zhang F, Song YQ, Jia SN, Zhu L, Fang SQ, Ge GB. Interactions of drug-metabolizing enzymes with the Chinese herb Psoraleae Fructus. Chin J Nat Med. 2019;17(11):858–70.PubMed
23.
24.
Matuszewski BK, Constanzer ML, Chavez-Eng CM. Matrix effect in quantitative LC/MS/MS analyses of biological fluids: a method for determination of finasteride in human plasma at picogram per milliliter concentrations. Anal Chem. 1998;70(5):882–9.PubMed
25.
Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22(3):659–61.PubMed
26.
Guo B, Li C, Wang G, Chen L. Rapid and direct measurement of free concentrations of highly protein-bound fluoxetine and its metabolite norfluoxetine in plasma. Rapid Commun Mass Spectrom. 2006;20(1):39–47.PubMed
27.
He W, Wu JJ, Ning J, Hou J, Xin H, He YQ, Ge GB, Xu W. Inhibition of human cytochrome P450 enzymes by licochalcone A, a naturally occurring constituent of licorice. Toxicol In Vitro. 2015;29(7):1569–76.PubMed
28.
Xin H, Qi XY, Wu JJ, Wang XX, Li Y, Hong JY, He W, Xu W, Ge GB, Yang L. Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases. Food Chem Toxicol. 2016;90:112–22.PubMed
29.
Huang LH, Zhong YM, Xiong XH, Cen MF, Cheng XG, Wang GX, Chen JS, Wang SJ. The disposition of oxymatrine in the vascularly perfused rat intestine-liver preparation and its metabolism in rat liver microsomes. J Pharm Sci. 2016;105(2):897–903.PubMed
30.
Lin P, Dai Y, Yao Z, Qin Z, He L, Wang Q, Wei Z, Zhang Y, Yao X. Metabolic profiles and pharmacokinetics of Qingre Xiaoyanning capsule, a traditional Chinese medicine prescription of Sarcandrae Herba, in rats by UHPLC coupled with quadrupole time-of-flight tandem mass spectrometry. J Sep Sci. 2019;42(4):784–96.PubMed
31.
Liu XW, Yang JL, Niu W, Jia WW, Olaleye OE, Wen Q, Duan XN, Huang YH, Wang FQ, Du FF, Zhong CC, Li YF, Xu F, Gao Q, Li L, Li C. Human pharmacokinetics of ginkgo terpene lactones and impact of carboxylation in blood on their platelet-activating factor antagonistic activity. Acta Pharmacol Sin. 2018;39(12):1935–46.PubMedPubMedCentral
32.
Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10(7):1093–5.PubMed
33.
Halim CE, Xinjing SL, Fan L, Bailey Vitarbo J, Arfuso F, Tan CH, Narula AS, Kumar AP, Sethi G, Ahn KS. Anti-cancer effects of oxymatrine are mediated through multiple molecular mechanism(s) in tumor models. Pharmacol Res. 2019;147:104327.PubMed
34.
Rashid HU, Xu Y, Muhammad Y, Wang L, Jiang J. Research advances on anticancer activities of matrine and its derivatives: an updated overview. Eur J Med Chem. 2019;161:205–38.PubMed
35.
Li L, Hou X, Xu R, Liu C, Tu M. Research review on the pharmacological effects of astragaloside IV. Fundam Clin Pharmacol. 2017;31(1):17–36.PubMed
36.
Mancuso C, Santangelo R. Panax ginseng and Panax quinquefolius: from pharmacology to toxicology. Food Chem Toxicol. 2017;107(Pt A):362–72.PubMedPubMedCentral
37.
Liu W, Shi J, Zhu L, Dong L, Luo F, Zhao M, Wang Y, Hu M, Lu L, Liu Z. Reductive metabolism of oxymatrine is catalyzed by microsomal CYP3A4. Drug Des Devel Ther. 2015;9:5771–83.PubMedPubMedCentral
38.
Yang Z, Gao S, Yin T, Kulkarni KH, Teng Y, You M, Hu M. Biopharmaceutical and pharmacokinetic characterization of matrine as determined by a sensitive and robust UPLC-MS/MS method. J Pharm Biomed Anal. 2010;51(5):1120–7.PubMed
39.
Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286(5439):487.PubMed
40.
Miners JO, Mackenzie PI, Knights KM. The prediction of drug-glucuronidation parameters in humans: uDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro-in vivo extrapolation of drug clearance and drug-drug interaction potential. Drug Metab Rev. 2010;42(1):196–208.PubMed
41.
Seong SJ, Kang WY, Heo JK, Jo J, Choi WG, Liu KH, Lee S, Choi MK, Han YH, Lee HS, Ohk B, Lee HW, Song IS, Yoon YR. A comprehensive in vivo and in vitro assessment of the drug interaction potential of red ginseng. Clin Ther. 2018;40(8):1322–37.PubMed
42.
Pan X, Wang L, Gründemann D, Sweet DH. Inhibition of human organic cation transporters by the alkaloids matrine and oxymatrine. Fitoterapia. 2014;92:206–10.PubMed
43.
Li X, Hu J, Wang B, Sheng L, Liu Z, Yang S, Li Y. Inhibitory effects of herbal constituents on P-glycoprotein in vitro and in vivo: herb–drug interactions mediated via P-gp. Toxicol Appl Pharmacol. 2014;275(2):163–75.PubMed
44.
Zhang G, Ou R, Li F, Wu J, Zheng L, Tong Y, Liu Y, Liu Z, Lu L. Regulation of drug-metabolizing enzymes and efflux transporters by Astragali radix decoction and its main bioactive compounds: implication for clinical drug–drug interactions. J Ethnopharmacol. 2016;180:104–13.PubMed
45.
Zhang W, Liu M, Yang L, Huang F, Lan Y, Li H, Wu H, Zhang B, Shi H, Wu X. P-glycoprotein Inhibitor tariquidar potentiates efficacy of astragaloside IV in experimental autoimmune encephalomyelitis mice. Molecules. 2019;24(3):561.PubMedCentral
46.
Zhan T, Yao N, Wu L, Lu Y, Liu M, Liu F, Xiong Y, Xia C. The major effective components in Shengmai Formula interact with sodium taurocholate co-transporting polypeptide. Phytomedicine. 2019;59:152916.PubMed
47.
Lee S, Kwon M, Choi MK, Song IS. Effects of red ginseng extract on the pharmacokinetics and elimination of methotrexate via Mrp2 regulation. Molecules. 2018;23:2948.PubMedCentral
48.
Li N, Wang D, Ge G, Wang X, Liu Y, Yang L. Ginsenoside metabolites inhibit P-glycoprotein in vitro and in situ using three absorption models. Planta Med. 2014;80(4):290–6.PubMed
49.
Zhang Q, Li FJ, Jin RM, Song ZP. Study on the hepatotoxicity induced by matrine and oxymatrine. Chin Arch Tradit Chinese Medicine. 2011;29:1222–5.
Metadata
Title
Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug–drug interactions
Authors
Zifei Qin
Mengmeng Jia
Jing Yang
Han Xing
Zhao Yin
Zhihong Yao
Xiaojian Zhang
Xinsheng Yao
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Chinese Medicine / Issue 1/2020
Electronic ISSN: 1749-8546
DOI
https://doi.org/10.1186/s13020-020-00349-3

Other articles of this Issue 1/2020

Chinese Medicine 1/2020 Go to the issue

Research

A new fluorescent technique for pesticide detection by using metal coordination polymer and nanozyme

Review

Chinese herbal medicine for gout: a review of the clinical evidence and pharmacological mechanisms

Research

Dissecting the mechanism of Yuzhi Zhixue granule on ovulatory dysfunctional uterine bleeding by network pharmacology and molecular docking

Research

Exploring the protective effect of Modified Xiaochaihu Decoction against hepatic steatosis and inflammation by network pharmacology and validation in ageing rats

Research

Catechins from oolong tea improve uterine defects by inhibiting STAT3 signaling in polycystic ovary syndrome mice

Research

LC–MS-based multivariate statistical analysis for the screening of potential thrombin/factor Xa inhibitors from Radix Salvia Miltiorrhiza