Abstract：OBJECTIVE To investigate the effect of flavonoids and triterpenoids on the function of organic anion transporting polypeptide 1B3. METHODS Natural products such as flavonoids and triterpenoids are widely present in traditional Chinese medicine and daily diets. In the present study, CHO cells stably expressing OATP1B3 and its fluorescent substrate fluorescein methotrexate were employed to investigate the effect of 21 natural products on the function of OATP1B3. RESULTS Mulberrin, glycyrrhetinic acid, glycyrrhizic acid, quercitrin, quercetin, and chrysanthemum stem-leaf flavonoids showed significant inhibitory effects on OATP1B3-mediated uptake of fluorescein methotrexate, with IC50 values being of 3.6, 3.8, 7.5, 9.0, 10.1 μmol·L-1, and 4.1 μg·mL-1, respectively. The IC50 value of glycyrrhetinic acid on OATP1B3 was comparable to its blood concentration in clinics, indicating an OATP1B3-mediated drug-drug interaction could occur. CONCLUSION Some flavonoids and triterpenoids are OATP1B3 inhibitors. When patients take medications of OATP1B3 substrates, care should be taken to avoid coadmistration of drugs or food containing these inhibitors to circumvent the occurrence of adverse drug interactions.
金梦, 向轶群, 杨静杰, 贵春山. 黄酮和三萜类化合物对有机阴离子转运多肽1B3功能的影响[J]. 中国药学杂志, 2020, 55(18): 1512-1516.
JIN Meng, XIANG Yi-qun, YANG Jing-jie, GUI Chun-shan. Effect of Flavonoid and Triterpenoid Compounds on the Function of Organic Anion Transporting Polypeptide 1B3. Chinese Pharmaceutical Journal, 2020, 55(18): 1512-1516.
HAGENBUCH B, GUI C. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family[J]. Xenobiotica, 2008, 38(7-8): 778-801.
[2]
SHI M Z, LIU Y, BIAN J L, et al. The interactions between natural products and OATP1B1[J]. Acta Pharm Sin(药学学报), 2015, 50(7): 848-853.
[3]
WEN F, SHI M, BIAN J, et al. Identification of natural products as modulators of OATP2B1 using LC-MS/MS to quantify OATP-mediated uptake[J]. Pharm Biol, 2016, 54(2): 293-302.
[4]
GUI C, MIAO Y, THOMPSON L, et al. Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3[J]. Eur J Pharmacol, 2008, 584(1): 57-65.
[5]
GUI C, HAGENBUCH B. Amino acid residues in transmembrane domain 10 of organic anion transporting polypeptide 1B3 are critical for cholecystokinin octapeptide transport[J]. Biochemistry, 2008, 47(35): 9090-9097.
[6]
HAGENBUCH B, MEIER P J. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties[J]. Pflugers Arch, 2004, 447(5): 653-665.
[7]
HAGENBUCH B, MEIER P J. The superfamily of organic anion transporting polypeptides[J]. Biochim Biophys Acta, 2003, 1609(1): 1-18.
[8]
KOENEN A, KROEMER H K, GRUBE M, et al. Current understanding of hepatic and intestinal OATP-mediated drug-drug interactions[J]. Expert Rev Clin Pharmacol, 2011, 4(6): 729-742.
[9]
ALAM K, CROWE A, WANG X, et al. Regulation of organic anion transporting polypeptides (OATP) 1B1- and OATP1B3-mediated transport: an updated review in the context of OATP-mediated drug-drug interactions[J]. Int J Mol Sci, 2018, 19(3): 855.
[10]
CAZAROLLI L H, ZANATTA L, ALBERTON E H, et al. Flavonoids: prospective drug candidates[J]. Mini Rev Med Chem, 2008, 8(13): 1429-1440.
[11]
LIU P, WANG G Q. Advances on pharmacological action of pentacyclic triterpenoids[J]. Strait Pharm J(海峡药学), 2018, 30(10): 1-6.
[12]
OBOLENTSEVA G V, LITVINENKO V I, AMMOSOV A S, et al. Pharmacological and therapeutic properties of licorice preparations (a review) [J]. Pharm Chem J, 1999, 33(8): 427-434.
[13]
KRAHENBUHL S, HASLER F, FREY B M, et al. Kinetics and dynamics of orally administered 18 beta-glycyrrhetinic acid in humans[J]. J Clin Endocrinol Metab, 1994, 78(3): 581-585.
[14]
MACKENZIE M A, HOEFNAGELS W H, JANSEN R W, et al. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers[J]. J Clin Endocrinol Metab, 1990, 70(6): 1637-1643.
[15]
AL-DUJAILI E A, KENYON C J, NICOL M R, et al. Liquorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vivo and in vitro by inhibiting adrenal SULT2A1 activity[J]. Mol Cell Endocrinol, 2011, 336(1-2): 102-109.
[16]
FARESE JR R V, BIGLIERI E G, SHACKLETON C H, et al. Licorice-induced hypermineralocorticoidism[J]. N Engl J Med, 1991, 325(17): 1223-1227.
2020, Vol. 55 
