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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Research Article

Effects of Astragaloside IV on the Pharmacokinetics of Metoprolol in Rats and its Mechanism

Author(s): Zhongbo Shi, Junhao Jiang, Dezhang Zhao, Baogang Xie, Yan Li and Chao Yu*

Volume 23, Issue 2, 2022

Published on: 07 March, 2022

Page: [131 - 136] Pages: 6

DOI: 10.2174/1389200223666220128143133

Price: $65

Abstract

Backgrond: Astragaloside IV (AST) and metoprolol are often used together to treat cardiovascular diseases, while the herb-drug interaction (HDI) between them is still unclear.

Objective: This study investigates the effect of AST on the pharmacokinetics of metoprolol in rats and its mechanism to predict the HDI.

Method: First, IC50 value of AST on nine CYP450 enzymes in human liver microsomes (HLMs) was determined by the cocktail method. We explored the effect of AST on the pharmacokinetics of metoprolol (metabolized by CYP2D6) in vivo. Twelve male SD rats were equally divided into two groups, with or without pretreatment of AST (3 mg/kg/day) for 7 days, and they received metoprolol (27 mg/kg) by oral administration. Blood samples were determined using HPLC. Finally, the mechanism of AST was explored.

Results: AST exhibited a moderate inhibitory effect on CYP2D6 with IC50 value of 32.28 μM. The pharmacokinetic parameters of metoprolol were significantly altered by AST with the increase of AUC0-∞ (538.81 ± 51.41 to 1088.34 ± 86.46 μg*min/mL, P<0.05) and Cmax (6.21 ± 0.56 to 8.34 ± 0.87 μg/ml, P<0.05). The investigation of the mechanism showed AST to be an irreversible inhibitor of CYP2D6 with KI value of 2.9 μM and Kinact of 0.018 min−1, respectively.

Conclusion: AST was found to increase the plasma exposure of metoprolol in rats. AST reduced the metabolism of metoprolol by inhibiting CYP2D6 activity. The HDI might enhance when metoprolol and AST will be applied in combination.

Keywords: Astragaloside IV, CYP2D6, herb-drug interaction, metoprolol, pharmacokinetics, irreversible inhibition.

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[1]
Hsiao, W.L.; Liu, L. The role of traditional Chinese herbal medicines in cancer therapy--from TCM theory to mechanistic insights. Planta Med., 2010, 76(11), 1118-1131.
[http://dx.doi.org/10.1055/s-0030-1250186] [PMID: 20635308 ]
[2]
Zhou, S.F.; Zhou, Z.W.; Li, C.G.; Chen, X.; Yu, X.; Xue, C.C.; Herington, A. Identification of drugs that interact with herbs in drug development. Drug Discov. Today, 2007, 12(15-16), 664-673.
[http://dx.doi.org/10.1016/j.drudis.2007.06.004] [PMID: 17706549 ]
[3]
Borse, S.P.; Singh, D.P.; Nivsarkar, M. Understanding the relevance of herb-drug interaction studies with special focus on interplays: a prerequisite for integrative medicine. Porto Biomed. J., 2019, 4(2), e15.
[http://dx.doi.org/10.1016/j.pbj.0000000000000015] [PMID: 31595257 ]
[4]
Wang, X.; Wang, Y.G. Progress in treatment of gout using chinese and western medicine. Chin. J. Integr. Med., 2020, 26(1), 8-13.
[http://dx.doi.org/10.1007/s11655-019-3058-y] [PMID: 30659455 ]
[5]
Shimada, T.; Yamazaki, H.; Mimura, M.; Inui, Y.; Guengerich, F.P. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther., 1994, 270(1), 414-423.
[PMID: 8035341 ]
[6]
Patel, J.A.; Gohil, K.J. Warfarin-herb interactions: A review and study based on assessment of clinical case reports in literature. Bol. Latinoam. Caribe Plantas Med. Aromat., 2008, 7, 85-99.
[7]
Awortwe, C.; Makiwane, M.; Reuter, H.; Muller, C.; Louw, J.; Rosenkranz, B. Critical evaluation of causality assessment of herbdrug interactions in patients. Br. J. Clin. Pharmacol., 2018, 84(4), 679-693.
[http://dx.doi.org/10.1111/bcp.13490] [PMID: 29363155 ]
[8]
Lv, L.; Wu, S.Y.; Wang, G.F.; Zhang, J.J.; Pang, J.X.; Liu, Z.Q.; Xu, W.; Wu, S.G.; Rao, J.J. Effect of astragaloside IV on hepatic glucoseregulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin. Phytother. Res., 2010, 24(2), 219-224.
[http://dx.doi.org/10.1002/ptr.2915] [PMID: 19610026 ]
[9]
Zhang, W.D.; Chen, H.; Zhang, C.; Liu, R.H.; Li, H.L.; Chen, H.Z. Astragaloside IV from Astragalus membranaceus shows cardioprotection during myocardial ischemia in vivo and in vitro. Planta Med., 2006, 72(1), 4-8.
[http://dx.doi.org/10.1055/s-2005-873126] [PMID: 16450288 ]
[10]
Huang, X.; Tang, L.; Wang, F.; Song, G. Astragaloside IV attenuates allergic inflammation by regulation Th1/Th2 cytokine and enhancement CD4(+)CD25(+)Foxp3 T cells in ovalbumin-induced asthma. Immunobiology, 2014, 219(7), 565-571.
[http://dx.doi.org/10.1016/j.imbio.2014.03.005] [PMID: 24731407 ]
[11]
Jiang, P.; Ma, D.; Wang, X.; Wang, Y.; Bi, Y.; Yang, J.; Wang, X.; Li, X.; Astragaloside, I.V. Astragaloside IV prevents obesity-associated hypertension by improving pro-inflammatory reaction and leptin resistance. Mol. Cells, 2018, 41(3), 244-255.
[PMID: 29562733 ]
[12]
Qin, H.; Liu, P.; Lin, S. Effects of Astragaloside IV on the SDF- 1/CXCR4 Expression in Atherosclerosis of apoE(-/-) Mice Induced by Hyperlipaemia. Evid. Based Complement. Alternat. Med., 2015, 2015, 385154.
[http://dx.doi.org/10.1155/2015/385154] [PMID: 26074989 ]
[13]
Zhang, W.D.; Zhang, C.; Liu, R.H.; Li, H.L.; Zhang, J.T.; Mao, C.; Moran, S.; Chen, C.L. Preclinical pharmacokinetics and tissue distribution of a natural cardioprotective agent astragaloside IV in rats and dogs. Life Sci., 2006, 79(8), 808-815.
[http://dx.doi.org/10.1016/j.lfs.2006.02.032] [PMID: 16564551 ]
[14]
Zhang, Y.H.; Zhang, Y.J.; Guo, Y.L.; Li, W.J.; Yu, C. Astragaloside IV inhibited the activity of CYP1A2 in liver microsomes and influenced theophylline pharmacokinetics in rats. J. Pharm. Pharmacol., 2013, 65(1), 149-155.
[http://dx.doi.org/10.1111/j.2042-7158.2012.01579.x] [PMID: 23215698 ]
[15]
Yancy, C.W.; Jessup, M.; Bozkurt, B.; Butler, J.; Casey, D.E., Jr; Drazner, M.H.; Fonarow, G.C.; Geraci, S.A.; Horwich, T.; Januzzi, J.L.; Johnson, M.R.; Kasper, E.K.; Levy, W.C.; Masoudi, F.A.; McBride, P.E.; McMurray, J.J.; Mitchell, J.E.; Peterson, P.N.; Riegel, B.; Sam, F.; Stevenson, L.W.; Tang, W.H.; Tsai, E.J.; Wilkoff, B.L. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol., 2013, 62(16), e147-e239.
[http://dx.doi.org/10.1016/j.jacc.2013.05.019] [PMID: 23747642 ]
[16]
Johnson, J.A.; Burlew, B.S. Metoprolol metabolism via cytochrome P4502D6 in ethnic populations. Drug Metab. Dispos., 1996, 24(3), 350-355.
[PMID: 8820427 ]
[17]
Swaisland, H.C.; Ranson, M.; Smith, R.P.; Leadbetter, J.; Laight, A.; McKillop, D.; Wild, M.J. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin. Pharmacokinet., 2005, 44(10), 1067-1081.
[http://dx.doi.org/10.2165/00003088-200544100-00005] [PMID: 16176119 ]
[18]
Tan, Y.Q.; Chen, H.W.; Li, J.; Astragaloside, I.V.; Astragaloside, I.V: An effective drug for the treatment of cardiovascular diseases. Drug Des. Devel. Ther., 2020, 14, 3731-3746.
[http://dx.doi.org/10.2147/DDDT.S272355] [PMID: 32982178 ]
[19]
Mo, Y.Y. Metoprolol in the treatment of cardiovascular disease: clinical analysis of 86 cases; Chinese J. Med. Guide, 2013.
[20]
Xu, T.; Bao, S.; Geng, P.; Luo, J.; Yu, L.; Pan, P.; Chen, Y.; Hu, G. Determination of metoprolol and its two metabolites in human plasma and urine by high performance liquid chromatography with fluorescence detection and its application in pharmacokinetics. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2013, 937, 60-66.
[http://dx.doi.org/10.1016/j.jchromb.2013.08.017] [PMID: 24018320 ]
[21]
Challa, S.R.; Challa, V.R.; Ragam, S.K. Quercetin declines plasma exposure of metoprolol tartrate in the rat model. J. Adv. Pharm. Technol. Res., 2014, 5(4), 185-190.
[http://dx.doi.org/10.4103/2231-4040.143038] [PMID: 25364697 ]
[22]
Masimirembwa, C.M.; Thompson, R.; Andersson, T.B. In vitro high throughput screening of compounds for favorable metabolic properties in drug discovery. Comb. Chem. High Throughput Screen., 2001, 4(3), 245-263.
[http://dx.doi.org/10.2174/1386207013331101] [PMID: 11375740 ]
[23]
Shan, W.; Zhang, Y.; Zhu, J.; Shao, Q.; Fan, X. Inhibitory effects of astragaloside IV on cytochrome P450 enzyme of rat liver microsomes. Zhongguo Zhongyao Zazhi, 2012, 37(1), 85-88.
[PMID: 22741468 ]
[24]
Venkatakrishnan, K.; Obach, R.S.; Rostami-Hodjegan, A. Mechanismbased inactivation of human cytochrome P450 enzymes: strategies for diagnosis and drug-drug interaction risk assessment. Xenobiotica, 2007, 37(10-11), 1225-1256.
[http://dx.doi.org/10.1080/00498250701670945] [PMID: 17968744]

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