Determination of Tissue Distribution of Alisol G, a CB1R Antagonist, in Rats by Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry

Chen-Yu Gao; Jian-Qiang Xi; Ding-Zhong Song; Jie Yuan; Wu-Si Hao; Zhong-Bao Cui; Zhi-Hong Cheng

doi:10.1055/s-0041-1724032

Pharmaceutical Fronts, Inhaltsverzeichnis

CC BY 4.0 · Pharmaceutical Fronts 2020; 02(04): e179-e187
DOI: 10.1055/s-0041-1724032

Original Article

Determination of Tissue Distribution of Alisol G, a CB1R Antagonist, in Rats by Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry

Chen-Yu Gao‡^*

¹Natural Products Pharm. Lab, National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Zhangjiang Hi-Tech Park, Pudong New District, Shanghai, People's Republic of China

,

Jian-Qiang Xi‡^*

¹Natural Products Pharm. Lab, National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Zhangjiang Hi-Tech Park, Pudong New District, Shanghai, People's Republic of China

,

Ding-Zhong Song

¹Natural Products Pharm. Lab, National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Zhangjiang Hi-Tech Park, Pudong New District, Shanghai, People's Republic of China

,

Jie Yuan

¹Natural Products Pharm. Lab, National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Zhangjiang Hi-Tech Park, Pudong New District, Shanghai, People's Republic of China

,

Wu-Si Hao

¹Natural Products Pharm. Lab, National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Zhangjiang Hi-Tech Park, Pudong New District, Shanghai, People's Republic of China

,

Zhong-Bao Cui

¹Natural Products Pharm. Lab, National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Zhangjiang Hi-Tech Park, Pudong New District, Shanghai, People's Republic of China

,

Zhi-Hong Cheng^*

¹Natural Products Pharm. Lab, National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Zhangjiang Hi-Tech Park, Pudong New District, Shanghai, People's Republic of China

› Institutsangaben

Abstract

Peripheral CB1R blockers without crossing the blood–brain barrier (BBB) have demonstrated therapeutic benefits in metabolic syndromes, including obesity. Among them is Alisol G, a tetracyclic triterpene from Alismatis rhizoma (zexie), which can effectively reduce the weight of obese mice. Results from CP55940-induced [35_S] GTP_γS cannabinoid-type 1 receptor (CB1R) binding assay show an IC₅₀ of 34.8 μmol/L for Alisol G, implicating its role as a CB1R antagonist. The purpose of our study is to assess whether Alisol G could serve as a peripheral CB1R antagonist for obesity treatment. In this study, we build a simple, reliable, and sensitive method to detect the concentration of Alisol G in rat tissue by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The results showed that Alisol G was mainly distributed in intestinal midgut, mucosa and small intestine, with little brain exposure. We suggested that intestine may be the main acting sites of Alisol G. Through comparison of brain and blood concentrations of Alisol G, our data showed that Alisol G cannot penetrate the BBB easily. In conclusion, Alisol G may represent a peripheral CB1R antagonist for the further treatment of obesity.

Keywords

Alisol G - UHPLC-MS/MS - tissue distribution - blood–brain barrier

Volltext

Referenzen

References
1 Zhao J, Xi JQ, Zhang BB, Song DZ, Cheng ZH. Pharmacokinetics and blood-brain barrier permeability of CB1R partial antagonist alisol g in rats [in Chinese]. Chinese J Pharm 2020; 51 (01) 95-102
2 Wu YK, Yeh CF, Ly TW, Hung MS. A new perspective of cannabinoid 1 receptor antagonists: approaches toward peripheral CB1R blockers without crossing the blood-brain barrier. Curr Top Med Chem 2011; 11 (12) 1421-1429
3 Han JH, Shin H, Park JY. et al. A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice. FASEB J 2019; 33 (03) 4314-4326
4 Moreira FA, Crippa JAS. The psychiatric side-effects of rimonabant. Br J Psychiatry 2009; 31 (02) 145-153
5 Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007; 370 (9600): 1706-1713
6 Lin JH. CSF as a surrogate for assessing CNS exposure: an industrial perspective. Curr Drug Metab 2008; 9 (01) 46-59
7 Li WK, Zhang J, Xie LC. Handbook of LC-MS Bioanalysis: Best Practices, Experimental Protocols, and Regulations. 2nd ed.. Peking: Science Press; 2017: 335-345
8 Liu BX. Pharmacokinetics and Tissue Distribution Study of 3, 4′, 5-Trimethoxy-trans-stilbene in Rats. Hebei: Hebei Medicine University; 2018
9 Shi D, Zhan X, Yu X. et al. Inhibiting CB1 receptors improves lipogenesis in an in vitro non-alcoholic fatty liver disease model. Lipids Health Dis 2014; 13: 173
10 Kang A, Hao H, Zheng X. et al. Peripheral anti-inflammatory effects explain the ginsenosides paradox between poor brain distribution and anti-depression efficacy. J Neuroinflammation 2011; 8: 100
11 Nogueiras R, Veyrat-Durebex C, Suchanek PM. et al. Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes 2008; 57 (11) 2977-2991
12 Qiao L, Chen CS, Zhang SC. Significance of expression of fatty acid amide hydrolase in normal colon wall. World Chin J Digestology 2009; 17: 2266-2271
13 Capasso R, Matias I, Lutz B. et al. Fatty acid amide hydrolase controls mouse intestinal motility in vivo. Gastroenterology 2005; 129 (03) 941-951
14 Wei LW, Yuan Z, Zhao M, Han J, Gu C, Fu L. Effect of cannabinoid receptor 1 on lipid metabolism in diet- induced obese mice. Sichuan Dong Wu 2018; 37 (01) 51-56
15 Liang QW. Biopharmaceutics and Pharmacodynamics. 3rd ed.. Peking: Peoples Medical Publishing House; 2007: 119
16 Dasgupta A. Usefulness of monitoring free (unbound) concentrations of therapeutic drugs in patient management. Clin Chim Acta 2007; 377 (1–2): 1-13
17 Jing HM, Li GJ. Progress in structure, function and toxicological research of blood-cerebrospinal fluid barrier. Zhongguo Yaolixue Yu Dulixue Zazhi 2010; 24: 562-565
18 Xu W, Li X, Lin N. et al. Pharmacokinetics and tissue distribution of five major triterpenoids after oral administration of Rhizoma Alismatis extract to rats using ultra high-performance liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal 2017; 146: 314-323