Abstract
The root bark of Clausena harmandiana Pierre ex Guillaumin, Rutaceae, has been widely studied for its antimalarial activity, action against cancer cells, and stimulation of glucose uptake. Dentatin, nordentatin, heptaphylline, and 7-methoxyheptaphylline have been reported to exhibit biological activities. This study aimed to investigate the pharmacokinetic profiles and bioavailability of these four compounds in rats after the intravenous or oral administration of 500 mg/kg of C. harmandiana extract. Rat blood samples were withdrawn at various times, and the concentrations of the four compounds were quantified using HPLC. After oral administration, the blood concentration–time curves showed that 7-methoxyheptaphylline was absorbed significantly faster than dentatin, nordentatin, and heptaphylline. However, the clearance of 7-methoxyheptaphylline was 762.49 ± 33.92 ml/h, but for dentatin, nordentatin, and heptaphylline, their clearance values were 113–118 ml/h. The mean maximum blood concentration (Cmax) of the four compounds was 54–95 ng/ml. Their elimination half-lives were 6–8 h. All four bioactive components from C. harmandiana had high oral availability; the oral availabilities of dentatin, nordentatin, heptaphylline, and 7-methoxyheptaphylline were 34.10, 31.48, 37.81, and 45.23%, respectively. This study will be helpful for future animal studies and clinical trials.
Graphical Abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Chaichantipyuth C, Pummangura S, Naowsaran K, Thanyavuthi D, Anderson JE, McLaughlin JL (1988) Two new bioactive carbazole alkaloids from the root bark of Clausena harmandiana. J Nat Prod 51:1285–1288. https://doi.org/10.1021/np50060a044
Chatchawanchonteera A, Keeratikulapas P, Mungmai N, Chitsanoor S, Boottasri A, Kaenchumpa P, Wangboonsakul J (2009) Antimicrobial activity of Clausena harmandiana extract against bacteria isolated from dogs with otitis externa. KKU Vet J 19:48–55
Daodee S, Wangboonskul J, Yenjai C, Boonyarat C, Monthakantirat O (2012) Determination of five carbazole alkaloids from the root of Clausena harmandiana by high performance liquid chromatography. Isan J Pharm Sci 8:94–100
Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095. https://doi.org/10.1023/A:1018943613122
Feng C, Ruan JL, Cai YL (2010a) Simultaneous determination and pharmacokinetics of four coumarins in rat plasma after oral administration of traditional Chinese medicine “YIGONG” capsule by SPE-HPLC. J Braz Chem Soc 21:2272–2277. https://doi.org/10.1590/S0103-50532010001200014
Feng L, Wang L, Jiang X (2010b) Pharmacokinetics, tissue distribution and excretion of coumarin components from Psoralea corylifolia L. in rats. Arch Pharm Res 33:225–230
Gasparetto JC, Peccinini RG, De Francisco TMG, Cerqueira LB, Campos FR, Pontarolo R (2015) A kinetic study of the main guaco metabolites using syrup formulation and the identification of an alternative route of coumarin metabolism in humans. PLoS ONE 10:e0118922. https://doi.org/10.1371/journal.pone.0118922
Jantamat P, Weerapreeyakul N, Puthongking P (2019) Cytotoxicity and apoptosis induction of coumarins and carbazole alkaloids from Clausena harmandiana. Molecules 24:3385. https://doi.org/10.3390/molecules24183385
Ma J, Shi J, Le H, Cho R, Huang JC, Miao S, Wong BK (2008) A fully automated plasma protein precipitation sample preparation method for LC-MS/MS bioanalysis. J Chromatogr B Anal Technol Biomed Life Sci 862:219–226. https://doi.org/10.1016/j.jchromb.2007.12.012
Maneerat W, Phakhodee W, Ritthiwigrom T, Cheenpracha S, Promgool T, Yossathera K, Deachathai S, Laphookhieo S (2012) Antibacterial carbazole alkaloids from Clausena harmandiana twigs. Fitoterapia 83:1110–1114. https://doi.org/10.1016/j.fitote.2012.04.026
Matos DM, Viana MR, Alvim MC, Carvalho LS, Leite LH, Da Silva Filho AA, Nascimento JWL (2018) Pharmacokinetic profile and oral bioavailability of kaurenoic acid from Copaifera spp. in rats. Fitoterapia 128:142–147. https://doi.org/10.1016/j.fitote.2018.05.013
Nillert N, Boonyarat C, Welbat JU, Bunreungthong K, Puthongking P, Pannangrong W (2022) Clausena harmandiana root extract attenuated cognitive impairments via reducing amyloid accumulation and neuroinflammation in Aβ(1-42)-induced rats. BMC Complement Med Ther 22:108. https://doi.org/10.1186/s12906-022-03591-4
Noipha K, Thongthoom T, Songsiang U, Boonyarat C, Yenjai C (2010) Carbazoles and coumarins from Clausena harmandiana stimulate glucose uptake in L6 myotubes. Diabetes Res Clin Pract 90:e67-671. https://doi.org/10.1016/j.diabres.2010.09.005
Qiao X, Ye M, Xiang C, Wang Q, Liu CF, Miao WJ, Guo DA (2012) Analytical strategy to reveal the in vivo process of multi-component herbal medicine: a pharmacokinetic study of licorice using liquid chromatography coupled with triple quadrupole mass spectrometry. J Chromatogr A 1258:84–93. https://doi.org/10.1016/j.chroma.2012.08.041
Satyavarapu EM, Sinha PK, Mandal C (2020) Preclinical development of mahanine-enriched fraction from Indian spice Murraya koenigii for the management of cancer: efficacy, temperature/pH stability, pharmacokinetics, acute and chronic toxicity (14–180 days) studies. Biomed Res Int 2020:4638132. https://doi.org/10.1155/2020/4638132
Songsiang U, Thongthoom T, Boonyarat C, Yenjai C (2011) Claurailas A-D, cytotoxic carbazole alkaloids from the roots of Clausena harmandiana. J Nat Prod 74:208–212. https://doi.org/10.1021/np100654m
Songsiang U, Thongthoom T, Zeekpudsa P, Kukongviriyapan V, Boonyarat C, Wangboonskul J, Yenjai C (2012) Antioxidant activity and cytotoxicity against cholangiocarcinoma of carbazoles and coumarins from Clausena harmandiana. Science Asia 38:75–81. https://doi.org/10.2306/scienceasia1513-1874.2012.38.075
Sriphana U, Thongsri Y, Prariyachatigul C, Pakawatchai C, Yenjai C (2013) Clauraila E from the roots of Clausena harmandiana and antifungal activity against Pythium insidiosum. Arch Pharm Res 36:1078–1083. https://doi.org/10.1007/s12272-013-0115-5
Sungthong B, Sithon K, Panyatip P, Tadtong S, Nunthaboot N, Puthongking P (2022) Quantitative analysis and in silico molecular docking screening for acetylcholinesterase inhibitor and ADME prediction of coumarins and carbazole alkaloids from Clausena harmandiana. Rec Nat Prod 16:358–369. https://doi.org/10.25135/rnp.288.2106-2112
Thongthoom T, Promsuwan P, Yenjai C (2011) Synthesis and cytotoxic activity of the heptaphylline and 7-methoxyheptaphylline series. Eur J Med Chem 46:3755–3761. https://doi.org/10.1016/j.ejmech.2011.05.041
Thongthoom T, Songsiang U, Phaosiri C, Yenjai C (2010) Biological activity of chemical constituents from Clausena harmandiana. Arch Pharm Res 33:675–680. https://doi.org/10.1007/s12272-010-0505-x
Wangboonskul J, Prawan A, Takthaisong P, Sasithornwetchakun W, Boonyarat C, Yenjai C, Mahakunakorn P (2012) Analgesic, anti-inflammatory, antipyretic activities and acute toxicity of the ethanolic extract of Clausena harmandiana Pierre in animals. J Asian Assoc Sch Pharm 1:159–169
Wangboonskul JD, Pummangura S, Chaichantipyuth C (1984) Five coumarins and a carbazole alkaloid from the root bark of Clausena harmandiana. J Am Chem Soc 47:1058–1059. https://doi.org/10.1021/ja00322a008
Yenjai C, Sripontan S, Sriprajun P, Kittakoop P, Jintasirikul A, Tanticharoen M, Thebtaranonth Y (2000) Coumarins and carbazoles with antiplasmodial activity from Clausena harmandiana. Planta Med 66:277–279. https://doi.org/10.1055/s-2000-8558
Yi T, Zhu L, Tang YN, Zhang JY, Liang ZT, Xu J, Zhao ZZ, Yu ZL, Bian ZX, Yang ZJ, Chen HB (2014) An integrated strategy based on UPLC-DAD-QTOF-MS for metabolism and pharmacokinetic studies of herbal medicines: Tibetan “Snow Lotus” herb (Saussurea laniceps), a case study. J Ethnopharmacol 153:701–713. https://doi.org/10.1016/j.jep.2014.03.031
Zhang Y, Huo M, Zhou J, Xie S (2010) PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed 99:306–314. https://doi.org/10.1016/j.cmpb.2010.01.007
Acknowledgements
The authors express their gratitude to the Faculty of Pharmacy, Mahasarakham University, Maha Sarakham, Thailand; the Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand; and the Northeast Laboratory Animal Center, Khon Kaen, Thailand for their facilities.
Funding
This study was funded by the Thailand Science Research and Innovation (grant number DBG6080006).
Author information
Authors and Affiliations
Contributions
CM and CB designed and directed the study; CM, BS, and PP performed the experiments. CM wrote the manuscript. All the authors discussed the results, commented on the manuscript, and approved the final manuscript.
Corresponding author
Ethics declarations
Ethical Approval
The animal protocols were reviewed and approved on January 22nd, 2019 (approval number: 1/62) by the Institutional Animal Care and Use Committee of Khon Kaen University, Thailand. Male Wistar rats weighing 267–323 g at age of 6–7 weeks were supplied by Nomura Siam International Co., Ltd., Thailand.
Conflict of Interest
The authors declare no competing interests.
Disclaimer
The views expressed in this study do not reflect the Thailand Science Research and Innovation.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Mekjaruskul, C., Sungthong, B., Puthongking, P. et al. Pharmacokinetics and Oral Bioavailability of Coumarins and Carbazole Alkaloids from Clausena harmandiana Root Bark in Rats. Rev. Bras. Farmacogn. 33, 1170–1176 (2023). https://doi.org/10.1007/s43450-023-00457-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s43450-023-00457-9