Absolute bioavailability, dose proportionality, and tissue distribution of rotundic acid in rats based on validated LC-QqQ-MS/MS method

Haihua Shang; Xiaohan Dai; Mi Li; Yueyi Kai; Zerong Liu; Min Wang; Quansheng Li; Yuan Gu; Changxiao Liu; Duanyun Si

doi:10.1016/j.jpha.2021.03.008

Volume 12 Issue 2

May 2022

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Article Navigation > Journal of Pharmaceutical Analysis > 2022 > 12(2): 278-286

Haihua Shang, Xiaohan Dai, Mi Li, Yueyi Kai, Zerong Liu, Min Wang, Quansheng Li, Yuan Gu, Changxiao Liu, Duanyun Si. Absolute bioavailability, dose proportionality, and tissue distribution of rotundic acid in rats based on validated LC-QqQ-MS/MS method[J]. Journal of Pharmaceutical Analysis, 2022, 12(2): 278-286. doi: 10.1016/j.jpha.2021.03.008

Citation:

Haihua Shang, Xiaohan Dai, Mi Li, Yueyi Kai, Zerong Liu, Min Wang, Quansheng Li, Yuan Gu, Changxiao Liu, Duanyun Si. Absolute bioavailability, dose proportionality, and tissue distribution of rotundic acid in rats based on validated LC-QqQ-MS/MS method[J]. Journal of Pharmaceutical Analysis, 2022, 12(2): 278-286. doi: 10.1016/j.jpha.2021.03.008

Citation:

Haihua Shang, Xiaohan Dai, Mi Li, Yueyi Kai, Zerong Liu, Min Wang, Quansheng Li, Yuan Gu, Changxiao Liu, Duanyun Si. Absolute bioavailability, dose proportionality, and tissue distribution of rotundic acid in rats based on validated LC-QqQ-MS/MS method[J]. Journal of Pharmaceutical Analysis, 2022, 12(2): 278-286. doi: 10.1016/j.jpha.2021.03.008

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Absolute bioavailability, dose proportionality, and tissue distribution of rotundic acid in rats based on validated LC-QqQ-MS/MS method

doi: 10.1016/j.jpha.2021.03.008

Haihua Shang^a,b,
Xiaohan Dai^b,
Mi Li^b,
Yueyi Kai^b,
Zerong Liu^b,
Min Wang^b,
Quansheng Li^b,
Yuan Gu^b,c,
Changxiao Liu^{a,b
,
,},
Duanyun Si^{b,c
,
,}

a. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China;
b. State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300301, China;
c. Research Unit for Drug Metabolism, Chinese Academy of Medical Sciences, Tianjin, 300301, China

Funds:

This study was supported by CAMS Innovation Fund for Medical Sciences (Grant No.: 2019-I2M-5–020), the National Natural Science Foundation of China (Grant No.: 81503154), and the National Major Scientific and Technological Special Project for Significant New Drugs Development (Grant No.: 2017ZX09101002-001-005).

Received Date: Oct. 28, 2020
Accepted Date: Mar. 24, 2021
Rev Recd Date: Feb. 23, 2021
Publish Date: Mar. 30, 2021

Abstract

Abstract

Rotundic acid (RA), an ursane-type pentacyclic triterpene acid isolated from the dried barks of Ilex rotunda Thunb. (Aquifoliaceae), possesses diverse bioactivities. To further study its pharmacokinetics, a simple and sensitive liquid chromatography with triple quadrupole mass spectrometry (LC-QqQ-MS/MS) method was developed and validated to quantify RA concentration in rat plasma and tissue using etofesalamide as an internal standard (IS). Plasma and tissue samples were subjected to one-step protein precipitation. Chromatographic separation was achieved on a ZORBAX Eclipse XDB-C₁₈ column (4.6mm×50mm, 5μm) under gradient conditions with eluents of methanol:acetonitrile (1:1, V/V) and 5mM ammonium formate:methanol (9:1, V/V) at 0.5mL/min. Multiple reaction monitoring transitions were performed at m/z 487.30→437.30 for RA and m/z 256.10→227.10 for IS in the negative mode. The developed LC-QqQ-MS/MS method exhibited good linearity (2-500ng/mL) and was fully validated in accordance with U.S. Food and Drug Administration bioanalytical guidelines. Dose proportionality and bioavailability in rats were determined by comparing pharmacokinetic data after single oral (10, 20, and 40mg/kg) and intravenous (10mg/kg) administration of RA. Tissue distribution was studied following oral administration at 20mg/kg. The results showed that the absolute bioavailability of RA after administration at different doses ranged from 16.1% to 19.4%. RA showed good dose proportionality over a dose range of 10-40 mg/kg. RA was rapidly absorbed in a dose-dependent manner and highly distributed in the liver. In conclusion, this study is the first to systematically elucidate the absorption and distribution characteristics of RA in rats, which can provide additional information for further development and evaluation of RA in drug metabolism and pharmacokinetic studies.
- Rotundic acid,
- LC-QqQ-MS/MS,
- Bioavailability,
- Tissue distribution,
- Pharmacokinetics,
- Dose proportionality

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References(37)

References

Chinese Pharmacopoeia Commission [CPC], Pharmacopoeia of the People's Republic of China, China Medical Science Press, Beijing, 2020, pp. 325

Yaozhi Network Database of Chinese patent medicine prescription, China. https://db.yaozh.com/chufang/. (accessed 20 October 2020)

A.O. Aro, J.P. Dzoyem, M.D. Awouafack, et al., Fractions and isolated compounds from Oxyanthus speciosus subsp. stenocarpus (Rubiaceae) have promising antimycobacterial and intracellular activity, BMC Complement. Altern. Med. 19 (2019), 108

H.T. Nguyen, D.V. Ho, H.Q. Vo, et al., Antibacterial activities of chemical constituents from the aerial parts of Hedyotis pilulifera, Pharm. Biol. 55 (2017) 787-791

T.D. Thang, P.C. Kuo, C.S. Yu, et al., Chemical constituents of the leaves of Glochidion obliquum and their bioactivity, Arch. Pharm. Res. 34 (2011) 383-389

X.F. Cao, J.S. Wang, P.R. Wang, et al., Triterpenes from the stem bark of Mitragyna diversifolia and their cytotoxic activity, Chin. J. Nat. Medicines 12 (2014) 628-631

Y. Chen, Y.F. He, M.L. Nan, et al., Novel rotundic acid derivatives: synthesis, structural characterization and in vitro antitumor activity, Int. J. Mol. Med. 31 (2013) 353-360

Y.F. He, M.L. Nan, J.M. Sun, et al., Design, synthesis and cytotoxicity of cell death mechanism of rotundic acid derivatives, Bioorg. Med. Chem. Lett. 23 (2013) 2543-2547

Y.F. He, M.L. Nan, J.M. Sun, et al., Synthesis, characterization and cytotoxicity of new rotundic acid derivatives, Molecules 17 (2012) 1278-1291

Y.F. He, M.L. Nan, Y.W. Zhao, et al., Design, synthesis and evaluation of antitumor activity of new rotundic acid acylhydrazone derivatives, Z. Naturforsch. C 71 (2016) 95-103

W.J. Liu, Y.Y. Peng, H. Chen, et al., Triterpenoid saponins with potential cytotoxic activities from the root bark of Ilex rotunda Thunb., Chem. Biodivers. 14 (2017), e1600209

M.L. Nan, X. Wang, H.J. Li, et al., Rotundic acid induces Cas3-MCF-7 cell apoptosis through the p53 pathway, Oncol. Lett. 17 (2019) 630-637

G. Roy, S. Guan, H.X. Liu, et al., Rotundic acid induces DNA damage and cell death in hepatocellular carcinoma through AKT/mTOR and MAPK pathways, Front. Oncol. 9 (2019), 545

Y.M. Hsu, Y.C. Hung, L.H. Hu, et al., Anti-diabetic effects of madecassic acid and rotundic acid, Nutrients 7 (2015) 10065-10075

Z.H. Yan, H. Wu, H.L. Yao, et al., Rotundic acid protects against metabolic disturbance and improves gut microbiota in type 2 diabetes rats, Nutrients 12 (2019), 67

Z.F. Wang, W.Y. Sun, D.H. Yu, et al., Rotundic acid enhances the impact of radiological toxicity on MCF-7 cells through the ATM/p53 pathway, Int. J. Oncol. 53 (2018) 2269-2277

J. Bhattacharyya, M.Z. De Almeida, Isolation of the constituents of the root-bark of guettarda platypoda, J. Nat. Prod. 48 (1985) 148-149

N.C. Kim, A.E. Desjardins, C.D. Wu, et al., Activity of triterpenoid glycosides from the root bark of Mussaenda macrophylla against two oral pathogens, J. Nat. Prod. 62 (1999) 1379-1384

Y. Orihara, Y. Ebizuka, Production of triterpene acids by cell-suspension cultures of olea europaea, in: V.R. Preedy, R.R. Watson (Eds.), Olives and Olive Oil in Health and Disease Prevention, Academic Press, New York, 2010, pp. 341-347

J.B. Xie, Z.M. Bi, P. Li, HPLC-ELSD determination of triterpenoids and triterpenoid saponins in Ilex pupurea leaves, Acta pharm. Sin. 38 (2003) 534-536

B. Yang, H. Li, Q.F. Ruan, et al., A facile and selective approach to the qualitative and quantitative analysis of triterpenoids and phenylpropanoids by UPLC/Q-TOF-MS/MS for the quality control of Ilex rotunda, J. Pharm. Biomed. Anal. 157 (2018) 44-58

J.P. Zhu, B. Yang, T. Yang, et al., Simultaneous determination of four constituents in Cortex Ilicis Rotundae with HPLC, Tradit. Chin. Drug Res. Pharmaco. 26 (2015) 558-560

Y.F. He, Z.H. Wei, Y. Xie, et al., Potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting efflux transporter P-glycoprotein, J Pharm. Anal. 10 (2020) 178-186

D. Kang, Q.Q. Ding, Y.F. Xu, et al., Comparative analysis of constitutes and metabolites for traditional Chinese medicine using IDA and SWATH data acquisition modes on LC-Q-TOF MS, J Pharm. Anal. 10 (2020) 588-596

Y.N. Tang, Y.X. Pang, X.C. He, et al., UPLC-QTOF-MS identification of metabolites in rat biosamples after oral administration of Dioscorea saponins: A comparative study, J. Ethnopharmacol. 165 (2015) 127-140

T. Yi, L. Zhu, Y.N. Tang, et al., 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 (2014) 701-713

M.L. Liao, H.H. Shang, Y.Z. Li, et al., An integrated approach to uncover quality marker underlying the effects of Alisma orientale on lipid metabolism, using chemical analysis and network pharmacology, Phytomedicine 45 (2018) 93-104

Food and Drug Administration, Bioanalytical method validation guidance for Industry, U.S. department of health and human services, Food and Drug Administration Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), 2018

C.J. Briscoe, M.R. Stiles, D.S. Hage, System suitability in bioanalytical LC/MS/MS, J. Pharm. Biomed. Anal. 44 (2007) 484-491

I.H. Baek, Dose proportionality and pharmacokinetics of dronedarone following intravenous and oral administration to rat, Xenobiotica 49 (2019) 734-739

B. Smith, F. Vandenhende, K. DeSante, et al., Confidence interval criteria for assessment of dose proportionality, Pharm. Res. 17 (2000) 1278-1283

J. Hummel, S. McKendrick, C. Brindley, et al., Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion, Pharmaceut. Statist. 8 (2009) 38-49

M.L. Nan, Y.F. He, Y.W. Zhao, et al., Oral bioavailability study of rotundic acid in rats, China Pharm. 19 (2016) 1648-1650

B. Yang, H. Li, Q.F. Ruan, et al., Rapid profiling and pharmacokinetic studies of multiple potential bioactive triterpenoids in rat plasma using UPLC/Q-TOF-MS/MS after oral administration of Ilicis Rotundae Cortex extract, Fitoterapia 129 (2018) 210-219

B. Yang, H. Li, Q.F. Ruan, et al., Effects of gut microbiota and ingredient-ingredient interaction on the pharmacokinetic properties of rotundic acid and pedunculoside, Planta Med. 85 (2019) 729-737

B. Davies, T. Morris, Physiological parameters in laboratory animals and humans, Pharm. Res. 10 (1993) 1093-1095

K.W. Ward, L.M. Azzarano, W.E. Bondinell, et al., Preclinical pharmacokinetics and interspecies scaling of a novel vitronectin receptor antagonist, Drug Metab. Dispos. 27 (1999) 1232-1241

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