Search JIM Advanced Search

Journal of Integrative Medicine ›› 2015, Vol. 13 ›› Issue (3): 165-172.doi: 10.1016/S2095-4964(15)60173-X

• Research Article • Previous Articles     Next Articles

Effects of Ayurvedic Rasayana botanicals on CYP3A4 isoenzyme system

Swapnil P. Borsea, Bhagyashree B. Kambleb   

  1. a Symbiosis School of Biomedical Sciences, Symbiosis International University, Lavale, Pune-412115, Maharashtra, India
    b Department of Pharmacognosy, JSS College of Pharmacy, Rocklands Ootacmund-643001, Tamilnadu, India
  • Received:2014-10-09 Accepted:2015-01-24 Online:2015-05-10 Published:2015-05-15

Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic (PK-PD) herb-drug interactions (HDI). The present study focuses on the importance of and novel approach for assessing HDI in integrative medicine with case examples of two frequently-used Ayurvedic Rasayana botanicals.
The aqueous extracts of Asparagus racemosus (ARE) and Gymnema sylvester (GSE) were prepared as per Ayurvedic Pharmacopoeia of India. Chemoprofiling of these extracts was done using high-performance liquid chromatography (HPLC). Additionally, ARE was characterized for the presence of shatavarins IV and I using HPLC & mass spectroscopy respectively. Effects of ARE and GSE were investigated on rat liver microsome using testosterone probe drug assay. The changes in formation of metabolite (6-β hydroxy testosterone) were monitored on incubation of testosterone alone, testosterone with ketoconazole, ARE and GSE using HPLC. Half inhibitory concentration (IC50) was used to predict plausible HDI.
ARE and GSE showed no inhibition with IC50 values >1 000 μg/mL while the standard inhibitor ketoconazole completely abolished CYP3A4-dependent activity at 0.531 μg/mL and IC50 was found to be 0.036 μg/mL.
ARE and GSE prepared as per Ayurvedic Pharmacopoeia of India were found to be safe for CYP3A4-mediated inhibitory HDI in rats. Our in vitro study suggests the need of further in vivo investigation for HDI in order to provide clinical relevance.

Key words: Drugs, Chinese herbal, Ayurveda, Asparagus racemosus, Gymnema sylvester, Plant extracts, Cytochrome P-450 CYP3A, Herb-drug interactions

[1] Tiwari AK, Rao Madhusudana J . Diabetes mellitus and multiple therapeutic approaches of phytochemicals: Present status and future prospects. Current Sci, 2002,83(1):30-38
[2] Zhou S, Zhou ZW, Li CG, Chen X, Yu X, Xue CC, Herington A . Identification of drugs that interacts with herbs in drug development. Drug Discov Today, 2007,12(15-16):664-673
doi: 10.1016/j.drudis.2007.06.004 pmid: 17706549
[3] Chung VCH, Ma PHX, Tang TSK, Lau CH, Kim JH, Griffiths SM . Do patients tell their clinicians they are using both prescribed and over the counter allopathic and traditional medicines? Eur J Integr Med. 2011; 3(4):e289-e298.
doi: 10.1016/j.eujim.2011.09.008
[4] U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Guidance for industry drug interaction studies — study design, data analysis, implications for dosing, and labeling recommendations (draft guidance) (2012-02) [2014-09-15]. .
[5] Bertz RJ, Granneman GR . Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet, 1997,32(3):210-258
doi: 10.2165/00003088-199732030-00004
[6] Bopanaa N, Saxena S . Asparagus racemosus — ethnopharmacological evaluation and conservation needs. J Ethnopharmacol, 2007,110(1):1-15
doi: 10.1016/j.jep.2007.01.001 pmid: 17240097
[7] Vaidya S . Review on gymnema: an herbal medicine for diabetes management. Pharmacia, 2011,1(2):37-42
[8] Patil D, Gautam M, Gairola S, Jadhav S, Patwardhan B . Effect of botanical immunomodulators on human CYP3A4 inhibition: implications for concurrent use as adjuvants in cancer therapy. Integr Cancer Ther, 2014,13(2):167-175
doi: 10.1177/1534735413503551
[9] The Ayurvedic Formulary of India Part-I, PDF-Part ‘B’: 22. [ 2014-09-15]. . Arabic.
[10] World Health Organization. WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues. WHO Library Cataloguing-in-Publication Data 2007. (2007)[ 2014-09-15]. .
[11] Patil D, Gautam M, Jadhav SS, Patwardhan B. HPLCESI-MS/MS based determination of steroidal saponins in complex matrices. In: International Seminar on Herbal Drug Research: Present and Future Prospects. December 4-5, 2009; Ooty, Tamil Nadu, India.
[12] Kamble B, Gupta A, Patil D, Janarao S, Khatal L, Duriaswamy B . Determination of gymnemagenin in extracts and marketed formulation of Gymnema sylvestre using HPLC-ESI-MS/MS method. Phytochem Anal, 2013,24(2):135-140
doi: 10.1002/pca.v24.2
[13] Ponnusankar S, Pandit S, Babu R, Bandyopadhyay A, Mukherjee PK . Cytochrome P450 inhibitory potential of Triphala — a Rasayana from Ayurveda. J Ethnopharmacol, 2011,133(1):120-125
doi: 10.1016/j.jep.2010.09.022 pmid: 20883765
[14] Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ . Protein measurement with Folin phenol reagent. J Biol Chem, 1951,193(1):265-275
[15] Lee CA, Kadwell SH, Kost TA, Serabjit-Singh CJ . CYP3A4 expressed by insect cells infected with a recombinant baculovirus containing both CYP3A4 and human NADPH-cytochrome P450 reductase is catalytically similar to human liver microsomal CYP3A4. Arch Biochem Biophys, 1995,319(1):157-167
doi: 10.1006/abbi.1995.1278
[16] Li XF, Ma MS, Cheng A, Zheng J, Tam YK . Determination of testosterone and its metabolites using liquid chromatography with elevated column temperature and flow-rate gradient. Anal Chim Acta, 2002,457(2):165-171
doi: 10.1016/S0003-2670(02)00051-X
[17] Zhang L, Zhang YD, Zhao P, Huang SM . Predicting drug-drug interactions: an FDA perspective. AAPS J, 2009,11(2):300-306
doi: 10.1208/s12248-009-9106-3 pmid: 2691466
[18] Eagling VA, Tjia JF, Back DJ . Differential selectivity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes. Br J Clin Pharmacol, 1998,45(2):107-114
[19] von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS, Shader RI . In vitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction. J Clin Pharmacol, 1994,34(12):1222-1227
doi: 10.1002/j.1552-4604.1994.tb04735.x pmid: 7738219
[20] Nagamani, Suresh J, Ahuja J, Reddy V . Comparative phytochemical screening of Vatashunga, Shatavari and Shatapushpa claimed for Prajasthapana activity. Ann Biol Res, 2012,3(3):1294-1304
[21] Ganpati KS, Maroti RA, Madhukar SR, Veerkuman BN, Sunil MS . Parameters studied for development of Gymnema sylvestre leaf extracts: as injectable anti-diabetic. IJRAP, 2012,3(2):283-235
[22] Diwanay S, Gautam M, Patwardhan B . Cytoprotection and immunomodulation in cancer therapy. Curr Med Chem Anticancer Agents, 2004,4(6):479-490
doi: 10.2174/1568011043352704 pmid: 15579014
[23] Multyplelabs. Analysis method of crude drug extract by HPLC. Analytical Technologies Ltd.[ 2014-09-02]. .
[24] Hayes PY, Jahidin AH, Lehmann R, Renman K, Kitching W, De Voss JJ . Structural revision of shatavarins I and IV, the major components from the roots of Asparagus racemosus. Tetrahedron Lett, 2006,47(39):6965-6969
doi: 10.1016/j.tetlet.2006.07.121
[25] Thangavelu D, Thangavelu T, Vembu T, Venkatachalam K, Selladurai E, Jegadeesan M . Pharmacognostic and phytochemical studies on Gymnema sylvestre R. Br. Hairy variant. Int J Pharm Phytopharmacol Res, 2012,2(3):143-147
[26] Racha JK, Zhao ZS, Olejnik N, Warner N, Chan R, Moore D, Satoh H . Substrate dependent inhibition profiles of fourteen drugs on CYP3A4 activity measured by a high throughput LCMS/MS method with four probe drugs, midazolam, testosterone, nifedipine and terfenadine. Drug Metab Pharmacokinet, 2003,18(2):128-138
doi: 10.2133/dmpk.18.128
[27] Turpeinen M, Korhonen LE, Tolonen A, Uusitalo J, Juvonen R, Raunio H, Pelkonen O . Cytochrome P450(CYP) inhibition screening: comparison of three tests. Eur J Pharm Sci, 2006,29(2):130-138
doi: 10.1016/j.ejps.2006.06.005
[28] Wienkers LC, Heath TG . Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov, 2005,4(10):825-833
doi: 10.1038/nrd1851 pmid: 16224454
[29] Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z . Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. J Clin Pharmacol, 2005,45(4):422-433
doi: 10.1177/0091270004273992
[30] Khaliq Y, Gallicano K, Venance S, Kravcik S, Cameron DW . Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus. Clin Pharmacol Ther, 2000,68(6):637-646
doi: 10.1067/mcp.2000.112363
[31] Dutreix C, Peng B, Mehring G, Hayes M, Capdeville R, Pokorny R, Seiberling M . Pharmacokinetic interaction between ketoconazole and imatinib mesylate(Glivec) in healthy subjects. Cancer Chemother Pharmacol, 2004,54(4):290-294
[32] Arun V, Liju VB, Reena JJ, Parthipan B, Renuka C . Traditional remedies of Kani tribes of Kottoor reserve forest, Agasthayavanam, Thiruvananthapuram, Kerala. Indian J Tradit Know, 2007,6(4):589-594
[33] Patil D, Gautam M, Gairola S, Jadhav S, Patwardhan B . Effect of botanical immunomodulators on human CYP3A4 inhibition: implications for concurrent use as adjuvants in cancer therapy. Integr Cancer Ther, 2014,13(2):167-175
doi: 10.1177/1534735413503551
[1] Wan-jun Guo, Yi Wang, Yu Deng, Lin-yan Cheng, Xin Liu, Ruo-fan Xi, Sheng-jie Zhu, Xin-yi Feng, Liang Hua, Kan Ze, Jian-yong Zhu, Dong-jie Guo, Fu-lun Li. Therapeutic effects of the extract of Sancao Formula, a Chinese herbal compound, on imiquimod-induced psoriasis via cysteine-rich protein 61. Journal of Integrative Medicine, 2022, 20(4): 376-384.
[2] Shu-yi Chen, Qun-wei Chen, Liu-mei Shou, Hong Pan, Shan-ming Ruan, Zhe-hao Liang, Qi-jin Shu. Stevens-Johnson syndrome/toxic epidermal necrolysis successfully treated with Chinese herbal medicine Pi-Yan-Ning: A case report. Journal of Integrative Medicine, 2021, 19(6): 555-560.
[3] Xin Yin, Shu-bin Cai, Lan-ting Tao, Lu-ming Chen, Zhong-de Zhang, Su-hong Xiao, Arthur Yin Fan, Xu Zou. Recovery of a patient with severe COVID-19 by acupuncture and Chinese herbal medicine adjuvant to standard care. Journal of Integrative Medicine, 2021, 19(5): 460-466.
[4] Qing-lan Wang, Yan-yan Tao, Hong-dong Xie, Cheng-hai Liu, Ping Liu. Fuzheng Huayu recipe, a traditional Chinese compound herbal medicine, attenuates renal interstitial fibrosis via targeting the miR-21/PTEN/AKT axis. Journal of Integrative Medicine, 2020, 18(6): 505-513.
[5] Ming-sheng Lyu, De-ying Li, Shao-zhong Zhou, Cheng-jun Ban, Jun Yan. Adult-onset Still's disease successfully treated with Chinese herbal medicine: A case report with 15-month follow-up. Journal of Integrative Medicine, 2020, 18(6): 530-534.
[6] Arthur Yin Fan, Sherman Gu, Sarah Faggert Alemi, Research Group for Evidence-based Chinese Medicine. Chinese herbal medicine for COVID-19: Current evidence with systematic review and meta-analysis. Journal of Integrative Medicine, 2020, 18(5): 385-394.
[7] Bin Lan, Jin-wen Ge, Shao-wu Cheng, Xi-long Zheng, Jun Liao, Chao He, Zheng-qing Rao, Guo-zuo Wang. Extract of Naotaifang, a compound Chinese herbal medicine, protects neuron ferroptosis induced by acute cerebral ischemia in rats. Journal of Integrative Medicine, 2020, 18(4): 344-350.
[8] Deng-hai Zhang, Kun-lun Wu, Xue Zhang, Sheng-qiong Deng, Bin Peng. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. Journal of Integrative Medicine, 2020, 18(2): 152-158.
[9] Stefania Lamponi, Anna Maria Aloisi, Claudia Bonechi, Marco Consumi, Alessandro Donati, Gemma Leone, Claudio Rossi, Gabriella Tamasi, Luana Ghiandai, Ersilia Ferrini, Paolo Fiorenzani, Ilaria Ceccarelli, Agnese Magnani. Evaluation of in vitro cell and blood compatibility and in vivo analgesic activity of plant-derived dietary supplements. Journal of Integrative Medicine, 2019, 17(3): 213-220.
[10] Yoshimi Yamakami, Kyoko Morino, Yuki Takauji, Ryuichiro Kasukabe, Kensuke Miki, Mohammad Nazir Hossain, Dai Ayusawa, Michihiko Fujii. Extract of Emblica officinalis enhances the growth of human keratinocytes in culture. Journal of Integrative Medicine, 2019, 17(2): 141-146.
[11] Alexandra R. Vaughn, Aunna Pourang, Ashley K. Clark, Waqas Burney, Raja K. Sivamani . Dietary supplementation with turmeric polyherbal formulation decreases facial redness: a randomized double-blind controlled pilot study. Journal of Integrative Medicine, 2019, 17(1): 20-23.
[12] Supakanya Kumkarnjana, Rutt Suttisri, Ubonthip Nimmannit, Thongchai Koobkokkruad, Chutichot Pattamadilok, Nontima Vardhanabhuti . Anti-adipogenic effect of flavonoids from Chromolaena odorata leaves in 3T3-L1 adipocytes. Journal of Integrative Medicine, 2018, 16(6): 427-434.
[13] Rohitash Jamwal. Bioavailable curcumin formulations: A review of pharmacokinetic studies in healthy volunteers. Journal of Integrative Medicine, 2018, 16(6): 367-374.
[14] Shohini Chakraborty, Nashra Afaq, Neelam Singh, Sukanta Majumdar. Antimicrobial activity of Cannabis sativaThuja orientalis and Psidium guajava leaf extracts against methicillin-resistant Staphylococcus aureus. Journal of Integrative Medicine, 2018, 16(5): 350-357.
[15] Bruno José Martins Da Silva, Amanda Anastácia Pinto Hage, Edilene Oliveira Silva, Ana Paula Drummond Rodrigues. Medicinal plants from the Brazilian Amazonian region and their antileishmanial activity: A review. Journal of Integrative Medicine, 2018, 16(4): 211-222.
Full text



[1] Jin-rong Fu. Establishment of multivariate diagnosis and treatment system of modern gynecology of traditional Chinese medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 22-24
[2] Hao Li, Ming-jiang Yao, Wen-ming Zhao, Jie Guan, Lin-lin Cai, Ling Cui. A randomized, controlled, double-blind trial of Huannao Yicong capsule in senile patients with mild cognitive impairment. Journal of Chinese Integrative Medicine, 2008, 6(1): 25-31
[3] Zhi-chun Jin. Problems in establishing clinical guideline for integrated traditional Chinese and Western medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 5-8
[4] SUN Ming-yu, ZUO Jian, DUAN Ji-feng, HAN Jun, FAN Shi-ming, ZHANG Wei, ZHU Li-fang, YAO Ming-hui. Antitumor activities of kushen flavonoids in vivo and in vitro. Journal of Chinese Integrative Medicine, 2008, 6(1): 51-59
[5] Min Cheng, Qiong Feng, Shu-wen Qian, Hui Gao, Cui-qing Zhu. Preliminary assay of p-amyloid binding elements in heart-beneficial recipe. Journal of Chinese Integrative Medicine, 2008, 6(1): 68-72
[6] Ning-qun Wang, Liang-duo Jiang, Zong-xing Li. Research progress in asthma-related quality of life. Journal of Chinese Integrative Medicine, 2008, 6(1): 93-97
[7] Jing-yuan Mao, Chang-xiao Liu, Heng-he Wang, Guang-li Wei , Zhen-peng Zhang, Jie Xing, Wang Xian liang , Ying-fei Bi . Effects of Shenmai Injection on serum concentration and pharmacokinetics of digoxin in dogs with heart failure. Journal of Chinese Integrative Medicine, 2010, 8(11): 1070-1074
[8] Zhi-mei Wang, Bin Zhang. A study on translation of ellipses in Huangdi Neijing from perspective of hermeneutic theory. Journal of Chinese Integrative Medicine, 2010, 8(11): 1097-1100
[9] Gui Yu, Jie Wang. Thinking on building the network cardiovasology of Chinese medicine. Journal of Chinese Integrative Medicine, 2012, 10(11): 1206-1210
[10] Pedro Saganha João, Doenitz Christoph, Greten Tobias, Efferth Thomas, J. Greten Henry. Qigong therapy for physiotherapists suffering from burnout: a preliminary study. Journal of Chinese Integrative Medicine, 2012, 10(11): 1233-1239