Pharmacokinetics of Five Alkaloids and their Metabolites in Normal and Diabetic Rats after Oral Administration of Rhizoma coptidis

Abstract

Rhizoma coptidis has been clinically used for a long time for the treatment of various diseases in China, such as hypertension, diabetes, and inflammation. Previous studies have shown that alkaloid components of Rhizoma coptidis extract could be extensively metabolized and the metabolites were also considered to be the therapeutic material basis. However, until now, pharmacokinetic studies of the in vivo metabolites have not been revealed yet. The aim of the present study was to characterize the pharmacokinetics and excretions of five main alkaloids (berberine, jatrorrhizine, palmatine, epiberberine, and coptisine) and their seven metabolites (berberrubine, demethyleneberberine, jatrorrhizine-3-O-β-D-glucuronide, thalifendine-10-O-β-D-glucuronide, berberrubine-9-O-β-D-glucuronide, demethyleneberberine-2-O-sulfate, and demethyleneberberine-2-O-β-D-glucuronide) in rats after oral administration of Rhizoma coptidis extract. Meanwhile, comparative pharmacokinetics and excretions of these analytes in diabetic model rats were also investigated, since Rhizoma coptidis is widely used for the treatment of diabetes. Our results showed that the in vivo existing forms of alkaloid components were phase II metabolites, highlighting the glucuronidation metabolic pathway. In diabetic model rats, the utilization of Rhizoma coptidis alkaloids was significantly increased and the biotransformation of berberine into berberrubine was significantly inhibited.

Key words

Coptis chinensis - Ranunculaceae - pharmacokinetics - excretion - diabetic rats - phase II metabolites

Publikationsverlauf

Eingereicht: 17. März 2021

Angenommen nach Revision: 10. Mai 2021

Artikel online veröffentlicht:
10. Juni 2021

• References

• 1 Wang J, Wang L, Lou GH, Zeng HR, Hu J, Huang QW, Peng W, Yang XB. Coptidis Rhizoma: a comprehensive review of its traditional uses, botany, phytochemistry, pharmacology and toxicology. Pharm Biol 2019; 57: 193-225
• 2 Hou Q, He WJ, Wu YS, Hao HJ, Xie XY, Fu XB. Berberine: a traditional natural product with novel biological activities. Altern Ther Health Med 2020; 26: 20-27
• 3 Liu L, Li J, He Y. Multifunctional epiberberine mediates multi-therapeutic effects. Fitoterapia 2020; 147: 104771
• 4 Long J, Song J, Zhong L, Liao Y, Liu L, Li X. Palmatine: A review of its pharmacology, toxicity and pharmacokinetics. Biochimie 2019; 162: 176-184
• 5 Wu J, Luo Y, Deng D, Su S, Li S, Xiang L, Hu Y, Wang P, Meng X. Coptisine from Coptis chinensis exerts diverse beneficial properties: A concise review. J Cell Mol Med 2019; 23: 7946-7960
• 6 Meng FC, Wu ZF, Yin ZQ, Lin LG, Wang R, Zhang QW. Coptidis rhizoma and its main bioactive components: recent advances in chemical investigation, quality evaluation and pharmacological activity. Chin Med 2018; 13: 13
• 7 Gong Z, Chen Y, Zhang R, Wang Y, Yang Q, Guo Y, Weng X, Gao S, Wang H, Zhu X, Dong Y, Li Y, Wang Y. Pharmacokinetics of two alkaloids after oral administration of rhizoma coptidis extract in normal rats and irritable bowel syndrome rats. Evid Based Complement Alternat Med 2014; 2014: 1-8
• 8 Qian XC, Zhang L, Tao Y, Huang P, Li JS, Chai C, Li W, Di LQ, Cai BC. Simultaneous determination of ten alkaloids of crude and wine-processed Rhizoma Coptidis aqueous extracts in rat plasma by UHPLC-ESI-MS/MS and its application to a comparative pharmacokinetic study. J Pharm Biomed Anal 2015; 105: 64-73
• 9 Ren Y, Wang Z, Wu C, Dong H, Gan C, Fan L, Wang W, Yang C. Ultrahigh-performance liquid chromatography with tandem mass spectrometry for the determination of 10 alkaloids in beagle plasma after the oral administration of the three Coptidis rhizoma extracts. J Ethnopharmacol 2019; 239: 111896
• 10 Yu S, Pang X, Deng Y, Liu L, Liang Y, Liu X, Xie L, Wang G, Wang X. A sensitive and specific liquid chromatography mass spectrometry method for simultaneous determination of berberine, palmatine, coptisine, epiberberine and jatrorrhizine from Coptidis Rhizoma in rat plasma. Int J Mass Spectrom 2007; 268: 30-37
• 11 Feng X, Wang K, Hu X, Chai L, Cao S, Ding L, Qiu F. Systematic screening and characterization of absorbed constituents and in vivo metabolites in rats after oral administration of Rhizoma coptidis using UPLC-Q-TOF/MS. Biomed Chromatogr 2020; 34: e4919
• 12 Yang N, Sun RB, Chen XL, Zhen L, Ge C, Zhao YQ, He J, Geng JL, Guo JH, Yu XY, Fei F, Feng SQ, Zhu XX, Wang HB, Fu FH, Aa JY, Wang GJ. In vitro assessment of the glucose-lowering effects of berberrubine-9-O-beta-D-glucuronide, an active metabolite of berberrubine. Acta Pharmacol Sin 2017; 38: 351-361
• 13 Chen F, Li DY, Zhang B, Sun JY, Sun F, Ji X, Qiu JC, Parker RB, Laizure SC, Xu J. Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance?. Drug Metab Rev 2018; 50: 369-397
• 14 Cheng Q, Aleksunes LM, Manautou JE, Cherrington NJ, Scheffer GL, Yamasaki H, Slitt AL. Drug-metabolizing enzyme and transporter expression in a mouse model of diabetes and obesity. Mol Pharm 2008; 5: 77-91
• 15 Lam JL, Jiang Y, Zhang T, Zhang EY, Smith BJ. Expression and functional analysis of hepatic cytochromes P450, nuclear receptors, and membrane transporters in 10- and 25-week-old db/db mice. Drug Metab Dispos 2010; 38: 2252-2258
• 16 Ran Q, Wang J, Wang L, Zeng HR, Yang XB, Huang QW. Rhizoma coptidis as a potential treatment agent for type 2 diabetes mellitus and the underlying mechanisms: a review. Front Pharmacol 2019; 10: 805
• 17 Shi S, Klotz U. Age-related changes in pharmacokinetics. Curr Drug Metab 2011; 12: 601-610
• 18 Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 2009; 41: 67-76
• 19 Yu XT, Xu YF, Huang YF, Qu C, Xu LQ, Su ZR, Zeng HF, Zheng L, Yi TG, Li HL, Chen JP, Zhang XJ. Berberrubine attenuates mucosal lesions and inflammation in dextran sodium sulfate-induced colitis in mice. PLoS One 2018; 13: e0194069
• 20 Zhang P, Qiang X, Zhang M, Ma D, Zhao Z, Zhou C, Liu X, Li R, Chen H, Zhang Y. Demethyleneberberine, a natural mitochondria-targeted antioxidant, inhibits mitochondrial dysfunction, oxidative stress, and steatosis in alcoholic liver disease mouse model. J Pharmacol Exp Ther 2015; 352: 139-147
• 21 Xiao J, Högger P. Influence of diabetes on the pharmacokinetic behavior of natural polyphenols. Curr Drug Metab 2014; 15: 23-29
• 22 Dostalek M, Akhlaghi F, Puzanovova M. Effect of diabetes mellitus on pharmacokinetic and pharmacodynamic properties of drugs. Clin Pharmacokinet 2012; 51: 481-499
• 23 Yu S, Yu Y, Liu L, Wang X, Lu S, Liang Y, Liu X, Xie L, Wang G. Increased plasma exposures of five protoberberine alkaloids from Coptidis Rhizoma in streptozotocin-induced diabetic rats: is P-GP involved?. Planta Med 2010; 76: 876-881
• 24 Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57: 1470-1481
• 25 Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96: 1698-1705
• 26 Zhang X, Qiu F, Jiang J, Gao C, Tan Y. Intestinal absorption mechanisms of berberine, palmatine, jateorhizine, and coptisine: involvement of P-glycoprotein. Xenobiotica 2011; 41: 290-296
• 27 Imenshahidi M, Hosseinzadeh H. Berberine and barberry (Berberis vulgaris): A clinical review. Phytother Res 2019; 33: 504-523
• 28 Gravel S, Chiasson JL, Turgeon J, Grangeon A, Michaud V. Modulation of CYP450 activities in patients with type 2 diabetes. Clin Pharmacol Ther 2019; 106: 1280-1289
• 29 Runge-Morris MA. Regulation of expression of the rodent cytosolic sulfotransferases. FASEB J 1997; 11: 109-117
• 30 Shi R, Wu J, Meng C, Ma B, Wang T, Li Y, Ma Y. Cyp3a11-mediated testosterone-6beta-hydroxylation decreased, while UGT1a9-mediated propofol O-glucuronidation increased, in mice with diabetes mellitus. Biopharm Drug Dispos 2016; 37: 433-443
• 31 Fraquelli M, Pagliarulo M, Colucci A, Paggi S, Conte D. Gallbladder motility in obesity, diabetes mellitus and coeliac disease. Dig Liver Dis 2003; 35 (Suppl. 03) S12-S16
• 32 Shaw SJ, Hajnal F, Lebovitz Y, Ralls P, Bauer M, Valenzuela J, Zeidler A. Gallbladder dysfunction in diabetes mellitus. Dig Dis Sci 1993; 38: 490-496
• 33 Qiu F, Zhu Z, Kang N, Piao S, Qin G, Yao X. Isolation and identification of urinary metabolites of berberine in rats and humans. Drug Metab Dispos 2008; 36: 2159-2165
• 34 Feng X, Wang K, Cao S, Ding L, Qiu F. Pharmacokinetics and excretion of berberine and its nine metabolites in rats. Front Pharmacol 2021; 11: 594852