Pharmacokinetic Characteristics of Baicalin in Rats with 17α-ethynyl-estradiol-induced Intrahepatic Cholestasis

Abstract

Baicalin is one of the main active ingredients of choleretic traditional Chinese medicine drug Radix Scutellariae. The aim of this study was to explore the pharmacokinetic characteristics of baicalin in rats with 17α-ethynylestradiol (EE)-induced intrahepatic cholestasis (IC) based on its choleretic effects. Firstly, rats were subcutaneously injected with EE solution (5 mg/kg, 0.25 mL/100 g) for 5 consecutive days to construct an IC model. Then the bile excretion rate, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bile acid (TBA) and pathological changes of the liver were detected. Secondly, after successfully modeling, the rats were intragastrically given baicalin solution (200 mg/kg) (n=6). Blood samples were collected from the tail vein at different time points after intragastric administration. The protective effects of low- (50 mg/kg), medium- (100 mg/kg) and high-dose (200 mg/kg) baicalin on the liver in IC rats were evaluated. The content of baicalin in plasma was detected by liquid chromatography-mass spectrometry/mass spectrometry and pharmacokinetics parameters were calculated. Pharmacodynamic results showed that low-, medium- and high-dose baicalin all significantly increased the average excretion rate of bile (P<0.05), and significantly decreased serum levels of ALT, AST and ALP and TBA (P<0.05). Meanwhile, HE staining showed that baicalin significantly relieved EE-induced hepatocyte edema and necrosis. Pharmacokinetic results exhibited that the absorption of baicalin in both IC and normal control rats showed bimodal phenomenon. C_max, AU_(0-t) and AUC_(0-∞) of baicalin in IC rats were significantly higher than those of the normal control group (P<0.01). T_1/2 of plasma baicalin in the model group was significantly extended to (11.09±1.84) h, with clearance dropping to 61.78% of that of the normal control group (P<0.01). The above results suggested that baicalin had protective effects on the liver of IC rats, accompanied by significantly increased in vivo exposure, delayed in vivo clearance and markedly alterative pharmacokinetic characteristics. This study provides a theoretical basis for further development of baicalin as a feasible drug for treating IC.

Keywords

intrahepatic cholestasis / baicalin / 17α-ehynylestradiol / pharmacokinetics

References

[1] PataiaV, DixonPH, WilliamsonC. Pregnancy and bile acid disorders. Am J Physiol Gastrointest Liver Physiol, 2017, 313(1): G1-G6

[2] RielyCA, BacqY. Intrahepatic cholestasis of pregnancy. Clin Liver Dis, 2004, 8(1): 167-176

[3] SongX, VasilenkoA, ChenY, et al.. Transcriptional dynamics of bile salt export pump during pregnancy: mechanisms and implications in intrahepatic cholestasis of pregnancy. Hepatology, 2014, 60(6): 1993-2007

[4] JoshiD, JamesA, QuagliaA, et al.. Liver disease in pregnancy. Lancet, 2010, 375(9714): 594-605

[5] KotbMA. Ursodeoxycholic acid in neonatal hepatitis and infantile paucity of intrahepatic bile ducts: review of a historical cohort. Dig Dis Sci, 2009, 54(10): 2231-2241

[6] LinCC, ShiehDE. The anti-inflammatory activity of Scutellaria rivularis extracts and its active components, baicalin, baicalein and wogonin. Am J Chin Med, 1996, 24(1): 31-36

[7] RockwellS, GroveTA, LiuY, et al.. Preclinical studies of the Chinese Herbal Medicine formulation PHY906 (KD018) as a potential adjunct to radiation therapy. Int J Radiat Biol, 2013, 89(1): 16-25

[8] SunFJ, ChenHH, WangCF, et al.. Study on the cholaneresis of Chaihu and Huangqin. Zhong Cheng Yao (Chinese), 2011, 33(8): 1418-1420

[9] Chinese Pharmacopoeia Commission.. Chinese Pharmacopoeia of 2015 Edition. Beijing: The Medicine Science and Technology Press of China, 2015, 1: 301-302

[10] DindaB, DindaS, DasSharmaS, et al.. Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders. Eur J Med Chem, 2017, 131: 68-80

[11] ZhangY, HuangY, DengX, et al.. Iron overload-induced rat liver injury: Involvement of protein tyrosine nitration and the effect of baicalin. Eur J Pharmacol, 2012, 680: 95-101

[12] LiuLL, GongLK, WangH, et al.. Baicalin protects mouse from Concanavalin A-induced liver injury through inhibition of cytokine production and hepatocyte apoptosis. Liver Int, 2007, 27(4): 582-591

[13] ChoiYH, LeeYK, LeeMG. Effects of 17alpha-ethynylestradiol-induced cholestasis on the pharmacokinetics of doxorubicin in rats: reduced biliary excretion and hepatic metabolism of doxorubicin. Xenobiotica, 2013, 43(10): 901-907

[14] HongSS, ChoiJM, JinHE, et al.. Altered pharmacokinetics and hepatic uptake of TBuMA in ethynylestradiol-induced cholestasis. Arch Pharm Res, 2006, 29(4): 323-327

[15] HungDY, SiebertGA, ChangP, et al.. Hepatic pharmacokinetics of taurocholate in the normal and cholestatic rat liver. Br J Pharmacol, 2005, 145(1): 57-65

[16] LandmannL, AngermullerS, RahnerC, et al.. Expression, distribution, and activity of Na+,K+-ATPase in normal and cholestatic rat liver. J Histochem Cytochem, 1998, 46(3): 405-410

[17] YamamotoY, MooreR, HessHA, et al.. Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity. J Biol Chem, 2006, 281(24): 16625-16631

[18] CrocenziFA, PellegrinoJM, CataniaVA, et al.. Galactosamine prevents ethinylestradiol-induced cholestasis. Drug Metab Dispos, 2006, 34(6): 993-997

[19] CrocenziF S, PozziEJ, PellegrinoJM, et al.. Beneficial effects of Silymarin on estrogen-induced cholestasis in the rat: a study in vivo and in isolated hepatocyte couplets. Hepatology, 2001, 34(2): 329-339

[20] Rodriguez-GarayEA. Cholestasis: human disease and experimental animal models. Ann Hepatol, 2003, 2(4): 150-158

[21] LiuD, WuT, ZhangCL, et al.. Beneficial effect of Calculus Bovis Sativus on 17alpha-ethynylestradiol-induced cholestasis in the rat. Life Sei, 2014, 113(l-2): 22-30

[22] LiC, LinG, ZuoZ. Pharmacological effects and pharmacokinetics properties of Radix Scutellariae and its bioactive flavones. Biopharm Drug Dispos, 2011, 32(8): 427-445

[23] PengXD, DaiLL, HuangCQ, et al.. Correlation between anti-fibrotic effect of baicalin and serum cytokines in rat hepatic fibrosis. World J Gastroenterol, 2009, 15(37): 4720-4725

[24] de OliveiraMR, NabaviSF, HabtemariamS, et al.. The effects of baicalein and baicalin on mitochondrial function and dynamics: A review. Pharmacol Res, 2015, 100: 296-308

[25] LuT, SongJ, HuangF, et al.. Comparative pharmacokinetics of baicalin after oral administration of pure baicalin, Radix Scutellariae extract and-Huang-Lian-Jie-Du-Tang to rats. J Ethnopharmacol, 2007, 110(3): 412-418

[26] KimYH, JeongDW, KimYC, et al.. Pharmacokinetics of baicalein, baicalin and wogonin after oral administration of a standardized extract of Scutellaria baicalensis, PF-2405 in rats. Arch Pharm Res, 2007, 30(2): 260-265

[27] KangMJ, KoGS, OhDG, et al.. Role of metabolism by intestinal microbiota in pharmacokinetics of oral baicalin. Arch Pharm Res, 2014, 37(3): 371-378

[28] KamisakoT, OgawaH. Alteration of the expression of adenosine triphosphate-binding cassette transporters associated with bile acid and cholesterol transport in the rat liver and intestine during cholestasis. J Gastroenterol Hepatol, 2005, 20(9): 1429-1434

[29] MichelineD, EmmanuelJ, SergeE. Effect of Ursodeoxycholic Acid on the Expression of the Hepatocellular Bile Acid Transporters (Ntcp and bsep) in Rats With Estrogen-Induced Cholestasis. J Pediatr Gastroenterol Nutr, 2002, 35(2): 185-191

[30] RuizML, VillanuevaSS, LuquitaMG, et al.. Beneficial effect of spironolactone administration on ethynylestradiol-induced cholestasis in the rat: involvement of up-regulation of multidrug resistance-associated protein 2. Drug Metab Dispos, 2007, 35(11): 2060-2066

[31] CrocenziFA, D'AndreaV, CataniaVA, et al.. Prevention of Mrp2 activity impairment in ethinylestradiol-induced cholestasis by ursodeoxycholate in the rat. Drug Metab Dispos, 2005, 33(7): 888-891

[32] XiangD, WuT, FengCY, et al.. Upregulation of PDZK1 by Calculus Bovis Sativus May Play an Important Role in Restoring Biliary Transport Function in Intrahepatic Cholestasis. Evid Based Complement Alternat Med, 2017, 2017: 1640187

[33] AkaoT, HanadaM, SakashitaY, et al.. Efflux of baicalin, a flavone glucuronide of Scutellariae Radix, on Caco-2 cells through multidrug resistance-associated protein 2. J Pharm Pharmacol, 2007, 59(1): 87-93

[34] ZhangZQ, LiuaW, ZhuangL, et al.. Comparative pharmacokinetics of baicalin, wogonoside, baicalein and wogonin in plasma after oral administration of pure baicalin, radix Scutellariae and scutellariae-paeoniae couple extracts in normal and ulcerative colitis rats. Iran J Pharm Res, 2013, 12(3): 399-409

[35] ChangM J, XuYJ, HeWX, et al.. Intestinal injury in the rat model of 17alpha-ethynylestradiol-induced intrahepatic cholestasis. J Dig Dis, 2016, 17(11): 756-763

[36] GuinaneCM, CotterPD. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Therap Adv Gastroenterol, 2013, 6(4): 295-308

[37] KangMJ, KimHG, KimJS, et al.. The effect of gut microbiota on drug metabolism. Expert Opin Drug Metab Toxicol, 2013, 9(10): 1295-1308

[38] DengYX, ShiQZ, ChenB, et al.. Comparative pharmacokinetics of baicalin in normal and the type2 diabetic rats after oral administration of the Radix Scutellariae extract. Fitoterapia, 2012, 83(8): 1435-1442

[39] AssimakopoulosSF, ThomopoulosKC, PatsoukisN, et al.. Evidence for intestinal oxidative stress in patients with obstructive jaundice. Eur J Clin Invest, 2006, 36(3): 181-187

[40] AssimakopoulosSF, VagianosCE, PatsoukisN, et al.. Evidence for intestinal oxidative stress in obstructive jaundice-induced gut barrier dysfunction in rats. Acta Physiol Scand, 2004, 180(2): 177-185