Pharmacokinetics, Tissue Distribution and Plasma Protein Binding Studies of Rohitukine: A Potent Anti-hyperlipidemic Agent

Abstract

Rohitukine (RH) is a chromone alkaloid considered as one of the major active component of Dysoxylum binectariferum, exhibiting diverse pharmacological activities such as anti-hyperlipidemic, anti-cancer, anti-inflammatory, immuno-modulatory, anti-leishmanial, anti ulcer and anti-fertility. There’s still a lack of information of RH, inclusive of pharmacokinetics, tissue distribution and excretion, in vivo studies in experimental animals, such as hamster and rats. In this study, a selective and sensitive bioanalytical method was developed and validated using HPLC-UV system. The assay was applied to estimate pharmacokinetics, tissue distribution and excretion of RH in hamster at 50 mg/kg oral dose. It rapidly reached systemic circulation and distributed to various tissues, and highest concentration was observed in liver. The pharmacokinetic parameters such as clearance (CL/F) was 3.95±0.9 L/h/kg, volume of distribution (V_d/F) was 17.34±11.34 L/kg and elimination half-life was 2.62±1.34 h. RH shows moderate protein binding ~ 60% and found stable in gastro-intestinal fluid, a property that favors oral administration.

Key words

Rohitukine - Dysoxylum binectariferum - pharmacokinetics - HPLC-UV - plasma protein binding

• References

• 1 Aalbersberg W, Singh Y. Dammarane triterpenoids from Dysoxylum richii. Phytochemistry 1991; 30: 921-926
• 2 Singh S, Garg HS, Khanna NM. Dysobinin, a new tetranortriterpene from Dysoxylum binectariferum. Phytochemistry 1976; 15: 2001-2002
• 3 Khadem S, Marles RJ. Chromone and flavonoid alkaloids: occurrence and bioactivity. Molecules 2011; 17: 191-206
• 4 Naik RG, Kattige SL, Bhat SV et al. An antiinflammatory cum immunomodulatory piperidinylbenzopyranone from dysoxylum binectariferum: isolation, structure and total synthesis. Tetrahedron 1988; 44: 2081-2086
• 5 Harmon AD, Weiss U, Silverton JV. The structure of rohitukine, the main alkaloid of Amoora rohituka (Syn. Aphanamixis polystachya) (meliaceae). Tetrahedron Letters 1979; 20: 721-724
• 6 Yang D-H, Cai S-Q, Zhao Y-Y et al. A new alkaloid from Dysoxylum binectariferum. Journal of Asian Natural Products Research 2004; 6: 233-236
• 7 Dong Hui Y, CAI SQ, Yu Ying Z et al. Determination of the absolute configuration of rohitukine. Chinese Chemical Letters 2003; 14: 720-723
• 8 Mohana Kumara P, Zuehlke S, Priti V et al. Fusarium proliferatum, an endophytic fungus from Dysoxylum binectariferum Hook.f, produces rohitukine, a chromane alkaloid possessing anti-cancer activity. Antonie van Leeuwenhoek 2012; 101: 323-329
• 9 Ismail IS, Nagakura Y, Hirasawa Y et al. Chrotacumines A–D, Chromone Alkaloids from Dysoxylum acutangulum. Journal of Natural Products 2009; 72: 1879-1883
• 10 Keshri G, Oberoi RM, Lakshmi V et al. Contraceptive and hormonal properties of the stem bark of Dysoxylum binectariferum in rat and docking analysis of rohitukine, the alkaloid isolated from active chloroform soluble fraction. Contraception 2007; 76: 400-407
• 11 Lakshmi V, Pandey K, Kapil A et al. In vitro and in vivo leishmanicidal activity of Dysoxylum binectariferum and its fractions against Leishmania donovani. Phytomedicine 2007; 14: 36-42
• 12 Singh N, Singh P, Shrivastva S et al. Gastroprotective effect of anti-cancer compound rohitukine: possible role of gastrin antagonism and H+K+-ATPase inhibition. Naunyn-Schmiedeberg’s Archives of Pharmacology 2012; 385: 277-286
• 13 Mohanakumara P, Sreejayan N, Priti V et al. Dysoxylum binectariferum Hook.f (Meliaceae), a rich source of rohitukine. Fitoterapia 2010; 81: 145-148
• 14 Cragg GM, Newman DJ. Plants as a source of anti-cancer agents. J Ethnopharmacol 2005; 100: 72-79
• 15 Karp JE, Garrett-Mayer E, Estey EH et al. Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Haematologica 2012; 97: 1736-1742
• 16 Bible KC, Peethambaram PP, Oberg AL et al. North Central Cancer Treatment G A phase 2 trial of flavopiridol (Alvocidib) and cisplatin in platin-resistant ovarian and primary peritoneal carcinoma: MC0261. Gynecol Oncol 2012; 127: 55-62
• 17 Takada Y, Aggarwal BB. Flavopiridol inhibits NF-kappaB activation induced by various carcinogens and inflammatory agents through inhibition of IkappaBalpha kinase and p65 phosphorylation: abrogation of cyclin D1, cyclooxygenase-2, and matrix metalloprotease-9. J Biol Chem 2004; 279: 4750-4759
• 18 Sedlacek H, Czech J, Naik R et al. Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int J Oncol 1996; 9: 1143-1168
• 19 Ji J, Mould DR, Blum KA et al. A Pharmacokinetic/Pharmacodynamic Model of Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia Patients Treated with Flavopiridol. Clin Cancer Res 2013;
• 20 Nagasundaram N, George Priya Doss C. Predicting the Impact of Single-Nucleotide Polymorphisms in CDK2-Flavopiridol Complex by Molecular Dynamics Analysis. Cell Biochem Biophys 2013; 66: 681-695
• 21 Mishra S, Tiwari S, Shrivastava S et al. Pharmacological evaluation of the efficacy of Dysoxylum binectariferum stem bark and its active constituent rohitukine in regulation of dyslipidemia in rats. Journal of Natural Medicines 2014; 1-9
• 22 Varshney S, Shankar K, Beg M et al. Rohitukine inhibits in vitro adipogenesis arresting mitotic clonal expansion and improves dyslipidemia in vivo. Journal of Lipid Research 2014;
• 23 Chhonker YS, Chandasana H, Kumar D et al. Pharmacokinetic and metabolism studies of rohitukine in rats by high performance liquid-chromatography with tandem mass spectrometry. Fitoterapia 2014; 97: 34-42
• 24 FDA. Guidelines for industry: Bioanalytical method validation, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation And Research Center (CDER). 2001 www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070107.pdf
• 25 Srivastava P, Gupta RC. In situ absorption and protein binding characteristics of CDRI-85/92, an antiulcer pharmacophore. Int J Pharm 2003; 257: 97-102
• 26 Khurana M, Paliwal JK, Kamboj VP et al. Binding of centchroman with human serum as determined by charcoal adsorption method. Int J Pharm 1999; 192: 109-114
• 27 Shargel L, Yu ABC. Applied Biopharmaceutics & Pharmacokinetics. Appleton and Lange; Stamford: 1999