An Integrated in Silico-In Vitro-In Vivo Approach for Pharmacokinetic Studies of Andrographolide Using Aqueous Extract of Andrographis Paniculata (Burm.F.) Wall. Ex Nees
Keywords:
andrographolide, ADMET properties, herbal drug, pharmacokinetics
Abstract
Andrographis paniculata is a herbal plant that has been used traditionally for decades to treat a wide range of diseases. To this date, no research on the integration of in silico, in vitro, and in vivo pharmacokinetics (PK) has been documented on andrographolide (AG), the primary bioactive compound in A. paniculata. In this study, we employed an in silico approach to predict the physicochemical properties, metabolism, and toxicity of AG. PK properties were validated using in vitro assays and further tested in Wistar rats. Based on in silico prediction, AG demonstrated to be a soluble, permeant, and lipophilic drug. AG was regarded as a non-mutagenic and non-carcinogenic drug with a low risk of oral absorption. In vitro assays showed that AG was stable at all pH levels tested, had a high equilibrium solubility and moderately stable in the mouse plasma. AG was also permeant across the Caco-2 monolayer with Papp values of 9.627 × 10−6 cm/s (apical) and 18.1 × 10−6 cm/s (basolateral). It had a stable metabolism in the liver microsomes and did not have any inhibitory effects on the enzymes CYP2C8, CYP2C19, CYP2D6, or CYP3A4 (MDZ). Based on in vivo results, the volume of distribution and clearance were both high, with a short elimination half-life (0.17 ± 0.0 h) contributing to the low oral bioavailability (~2%). Rapid oral absorption was shown with Tmax of 0.25 h. Our data revealed promising drug-like properties of AG, and its pharmacokinetics profiles support its potential in developing andrographolide-based products from natural resources.
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Gong, P., Zhang, W., Zou, C., Han, S,. Tian, Q., Wang, J. et al. (2022). Andrographolide Attenuates Blood-Brain Barrier Disruption, Neuronal Apoptosis, and Oxidative Stress Through Activation of Nrf2/HO-1 Signalling Pathway in Subarachnoid Hemorrhage. Neurotoxicity Research, 40, 508–519. doi.org/10.1007/s12640-022-00486-7
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Jang, G.R., Harris, R.Z., Lau, D.T. (2001). Pharmacokinetics and its role in small molecule drug discovery research. Medicinal Research Reviews, 21, 382-396. doi:10.1002/med.1015
Jiang, M., Sheng, F., Zhang, Z., Ma, X., Gao, T., Fu, C. et al. (2021). Andrographis paniculata (Burm.f.) Nees and its major constituent andrographolide as potential antiviral agents. Journal of Ethnopharmacology, 272, 113954. doi:10.1016/j.jep.2021.113954
Kamiya, Y., Takaku, H., Yamada, R., Akase, C., Abe, Y., Sekiguchi, Y. et al. (2020). Determination and prediction of permeability across intestinal epithelial cell monolayer of a diverse range of industrial chemicals/drugs for estimation of oral absorption as a putative marker of hepatotoxicity. Toxicology Report, 7, 149-154. http://doi:10.1016/j.toxrep.2020.01.004
Khan, I., Mahfooz, S., Saeed, M., Ahmad, I., Ansari, I.A. (2021). Andrographolide Inhibits Proliferation of Colon Cancer SW-480 Cells via Downregulating Notch Signalling Pathway. Anticancer Agents in Medicinal Chemistry, 21, 487-97.
Knights, K.M., Stresser, D.M., Miners, J.O., Crespi, C.L. (2016). In Vitro Drug Metabolism Using Liver Microsomes. Current Protocols in Pharmacology, 74, 7.8.1–7.8.24. doi.org/10.1002/cpph.9
Kok-Yong, S., Lawrence, L. (2015). Drug Distribution and Drug Elimination. In (Ed.), Basic Pharmacokinetic Concepts and Some Clinical Applications. IntechOpen. doi.org/10.5772/59929
Konsoula, R., Jung, M. (2008). In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors. International Journal Pharmacy, 361, 19–25. doi.org/10.1016/j.ijpharm.2008.05.001
Liang, E., Liu, X., Du, Z., Yang, R., Zhao, Y. (2018). Andrographolide Ameliorates Diabetic Cardiomyopathy in Mice by Blockage of Oxidative Damage and NF-κB-Mediated Inflammation. Oxidative Medicine and Cell Longevity, 9086747. https://doi.org/10.1155/2018/9086747
Lin, T., Pan, K., Mordenti, J., Pan, L. (2007). In vitro assessment of cytochrome P450 inhibition: strategies for increasing LC/MS-based assay throughput using a one-point IC(50) method and multiplexing high-performance liquid chromatography. Journal of Pharmaceutical Science, 96, 2485–2493. doi.org/10.1002/jps.20884
Loureiro Damasceno, J.P., Silva da Rosa, H., Silva de Araújo, L., Jacometti Cardoso Furtado, N.A. (2022). Andrographis paniculata Formulations: Impact on Diterpene Lactone Oral Bioavailability. European Journal of Drug Metabolism and Pharmacokinetics, 47, 19–30. doi.org/10.1007/s13318-021-00736-7
Lu, J., Ma, Y., Wu, J., Huang, H., Wang, X., Chen, Z. et al. (2019). A review for the neuroprotective effects of andrographolide in the central nervous system. Biomedicine & Pharmacotherapy, 117, 109078.
Masimirembwa, C., Thelingwani, R. (2012). Application of In Silico, In Vitro and In Vivo ADMET/PK Platforms in Drug Discovery. In: Chibale, K., Davies-Coleman, M., Masimirembwa, C. (eds) Drug Discovery in Africa. Berlin, Heidelberg: Springer, pp. 151-191. doi.org/10.1007/978-3-642-28175-4_7
Morofuji, Y., Nakagawa, S. (2020). Drug Development for Central Nervous System Diseases Using In vitro Blood-brain Barrier Models and Drug Repositioning. Current Pharmaceutical Design, 26, 1466-1485.doi:10.2174/1381612826666200224112534
Nugroho, A.E., Lindawati, N.Y., Herlyanti, K., Widyastuti, L., Pramono, S. (2013). Anti-diabetic effect of a combination of andrographolide-enriched extract of Andrographis paniculata (Burm f.) Nees and asiaticoside-enriched extract of Centella asiatica L. in high fructose-fat fed rats. Indian Journal of Experimental Biology, 51, 1101–1108.
Pan, Y., Abd-Rashid, B.A., Ismail, Z., Ismail, R., Mak, J.W., Pook, P.C. et al. (2011). In vitro determination of the effect of Andrographis paniculata extracts and andrographolide on human hepatic cytochrome P450 activities. Journal of Natural Medicine, 65, 440-447. doi:10.1007/s11418-011-0516-z
Panossian, A., Hovhannisyan, A., Mamikonyan, G., Abrahamian, H., Hambardzumyan, E., Gabrielian, E. et al. (2000). Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine, 7, 351–364. doi.org/10.1016/S0944-7113(00)80054-9
Rajanna, M., Bharathi, B., Shivakumar, B.R., Deepak, M., Prashanth, D., Prabakaran, D. et al. (2021). Immunomodulatory effects of Andrographis paniculata extract in healthy adults - An open-label study. Journal of Ayurveda and Integrative Medicine, 12(3), 529-534. doi: 10.1016/j.jaim.2021.06.004.
Rozo, V., Quan, M., Aung, T., Kang, J., Thomasy, S.M., Leonard, B.C. (2022). Andrographolide Inhibits Corneal Fibroblast to Myofibroblast Differentiation In Vitro. Biomolecules, 12, 1447. doi.org/10.3390/biom12101447
Sa-ngiamsuntorn, K., Suksatu, A., Pewkliang, Y., Thongsri, P., Kanjanasirirat, P., Manopwisedjaroen, S. et al. (2021). Anti-SARS-CoV-2 Activity of Andrographis paniculata Extract and Its Major Component Andrographolide in Human Lung Epithelial Cells and Cytotoxicity Evaluation in Major Organ Cell Representatives. Journal of Natural Product, 84, 1261-1270. doi.org/10.1021/acs.jnatprod.0c01324
Seyedhosseini, G.H., Damavandi, M.S., Sadeghi, P., Massah, A.R., Hamidi Asl, T., Salari-Jazi, A. et al. (2022). Targeting and ultrabroad insight into molecular basis of Resistance-nodulation-cell division efflux pumps. Scientific Report, 12, 16130. doi.org/10.1038/s41598-022-20278-5
Sharifuddin, Y., Parry, E.M., Parry, J.M. (2012). The genotoxicity and cytotoxicity assessments of andrographolide in vitro. Food and Chemical Toxicology, 50, 1393–1398. doi.org/10.1016/j.fct.2012.01.039
Sinha, S. (2000). Raghuwanshi R. Evaluation of phytochemical, antioxidant and reducing activity in whole plant extract of Andrographis paniculata (Burm.f.) Wall. Ex Nees. Bioscience Biotechnology Research Communications, 13, 1734-1742.
Srinivasan, M.R., Preetha, S.P., Sudhakar, G.V., Tirumurugaan, K.G., Seshiah, A., Ramesh, S. (2021). Genotoxicity assessment of andrographolide in Ames mutagenicity assay and in vitro chromosomal aberration assay. Pharma Innovation, 10, 61-65.
Tang, J., Huber, A.D., Pineda, D.L., Boschert, K.N., Wolf, J.J., Kankanala, et al. (2019). 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors. European Journal of Medicinal Chemistry, 164, 179-192. doi:10.1016/j.ejmech.2018.12.047
Tuntland, T., Ethell, B., Kosaka, T., Blasco, F., Zang, R.X., Jain, M. et al. (2014). Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at Novartis Institute of Biomedical Research. Frontier Pharmacology, 5, 174. doi.org/10.3389/fphar.2014.00174
Turner, P.V., Brabb, T., Pekow, C., Vasbinder, M.A. (2011). Administration of substances to laboratory animals: routes of administration and factors to consider. Journal of the American Association for Laboratory Animal Science, 50(5), 600-613.
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Published
2024-08-16
How to Cite
Aljohani, G. F., Zakaria, N. H., Abdul Majid, F. A., Hudiyanti, D., & Anuar, M. N. N. (2024). An Integrated in Silico-In Vitro-In Vivo Approach for Pharmacokinetic Studies of Andrographolide Using Aqueous Extract of Andrographis Paniculata (Burm.F.) Wall. Ex Nees . Indonesian Journal of Pharmacy, 35(4), 599–612. https://doi.org/10.22146/ijp.12745
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Section
Research Article
