Hepatic Uptake Mechanism of Ophiopogonin D Mediated by Organic Anion Transporting Polypeptides.
OBJECTIVE
Ophiopogonin D (OPD) is one of the main active ingredients of SMI (Shenmai injection) which is widely used in clinical practice in China. Our previous study indicated  that OPD might be transported from blood into liver mediated by organic anion transporting polypeptides (OATPs/oatps). This study aims to explore the hepatic uptake mechanism of OPD in rat and human.


METHODS
Rosuvastatin (a competitive inhibitor of oatp1b2, oatp1a1, and oatp1a4), glycyrrhizic acid (a specific inhibitor of oatp1b2), digoxin (a specific inhibitor of oatp1a4), bromosulfophthalein (BSP), and ibuprofen (a specific inhibitor of oatp1a1) were used to study the uptake of OPD in rat hepatocytes. Furthermore, the uptake of OPD in human OATP1B1*1a-HEK293T cells was also investigated, and rosuvastatin, BSP, rifampin, and glycyrrhizic acid were all used as the competitive inhibitor of OATP1B1.


RESULTS
OPD can be taken in rat primary hepatocytes with Km(Michaelis Menten constant) of 8.10 μM and Vmax(maximum velocity) of 54.39 nmol/min/mg protein. The uptake of OPD in rat hepatocytes was inhibited significantly by rosuvastatin and glycyrrhizic acid. However, digoxin, BSP, and ibuprofen had no effect on the uptake of OPD in rat hepatocytes. OPD can also be transported by OATP1B1*1a-HEK293T cells with Kmof 5.50 μΜ and Vmaxof 29.07 nmol/min/mg protein. Compared with rosuvastatin, OPD has a higher affinity with OATP1B1 and can be transported faster in unit time. Rosuvastatin, BSP, rifampin, and glycyrrhizic acid all exhibited a certain extent inhibitory effect on the transport of OPD in OATP1B1*1a-HEK293T cells.


CONCLUSIONS
Overall, this study indicates OATP1B1 in human and oatp1b2 in rats might participate in the hepatic uptake of OPD.
Clinical Pharmacology Institute, Nanchang University, Bayi Road 461, Nanchang, 330006, People's Republic of China.|Chengdu Fifth People's Hospital, Chengdu, 611130, People's Republic of China.
Wen
W
Zhang
Jiangxi Health Occupation College, Nanchang, 330201, People's Republic of China.
Xiaomin
X
Xiong
Clinical Pharmacology Institute, Nanchang University, Bayi Road 461, Nanchang, 330006, People's Republic of China.
Lin
L
Chen
Clinical Pharmacology Institute, Nanchang University, Bayi Road 461, Nanchang, 330006, People's Republic of China.
Mingyi
M
Liu
Clinical Pharmacology Institute, Nanchang University, Bayi Road 461, Nanchang, 330006, People's Republic of China.
Yuqing
Y
Xiong
Clinical Pharmacology Institute, Nanchang University, Bayi Road 461, Nanchang, 330006, People's Republic of China.
Hong
H
Zhang
Clinical Pharmacology Institute, Nanchang University, Bayi Road 461, Nanchang, 330006, People's Republic of China.
Shibo
S
Huang
Clinical Pharmacology Institute, Nanchang University, Bayi Road 461, Nanchang, 330006, People's Republic of China. xch720917@163.com.
Chunhua
C
Xia
D000818:Animals; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D061251:Primary Cell Culture; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000493:pharmacokinetics*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013150:Spirostans / Q000493:pharmacokinetics*
D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; D012503:Saponins; C421207:Slco1b2 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013150:Spirostans; C046996:ophiopogonin D