Multiple ABC Transporters Efflux Baicalin

Abstract

Baicalein, the aglycone formed by hydrolysis of baicalin in the intestine, is well absorbed by passive diffusion but subjected to extensive intestinal glucuronidation. Efflux of baicalin, the low passive permeability glucuronide of baicalein from enterocytes, likely depends on a carrier-mediated transport. The present study was designed to explore potential drug-herb interaction by investigating the inhibitory effect of baicalin on the transport of reporter substrates by transporters and to identify the transporters responsible for the efflux of baicalin from enterocytes and hepatocytes. The interaction of baicalin with specific ABC transporters was studied using membranes from cells overexpressing human BCRP, MDR1, MRP2, MRP3 and MRP4. Baicalin was tested for its potential to inhibit vesicular transport by these transporters. The transport of baicalin by the selected transporters was also investigated. Transport by BCRP, MRP3 and MRP4 was inhibited by baicalin with an IC50 of 3.41 ± 1.83 μM, 14.01 ± 2.51 μM and 14.39 ± 5.69 μM respectively. Inhibition of MDR1 (IC50 = 94.84 ± 31.10 μM) and MRP2 (IC50 = 210.13 ± 110.49 μM) was less potent. MRP2 and BCRP are the apical transporters of baicalin that may mediate luminal efflux in enterocytes and biliary efflux in hepatocytes. The basolateral efflux of baicalin is likely mediated by MRP3 and MRP4 both in enterocytes and hepatocytes. Via inhibition of transport by ABC transporters, baicalin could interfere with the absorption and disposition of drugs.

Uptake and Transport Mechanism of Dihydromyricetin Across Human Intestinal Caco‐2 Cells

“…Therefore, DMY may be a substrate of MRP2 and BCRP but not P‐gp and MRP1. Previous reports revealed that the transport of flavonoids such as isorhamnetin, kaempferol (Zheng, Zhu, & Zhao, ) and baicalein (Kalapos‐Kovacs, Magda, & Jani, ) was also modulated by these 2 efflux transporters in Caco‐2 cells. Generally, because many transporters may have overlapping substrates (Seithel, Karlsson, Hilgendorf, Björquist, & Ungell, ), and because DMY is the substrate of MRP2 and BCRP or other potential transporters, the absorption of DMY in vivo may be more complicated than in vitro .…”

Baicalin is a substrate of OATP2B1 and OATP1B3

“…OATP2B1 may mediate absorption via cooperation of MRP3 and MRP4 basolaterally localized in the enterocytes (Zhang et al, ). In addition, it may cooperate with OATP1B3, and with BCRP and MRP2 expressed in the apical/canalicular membrane of hepatocytes to mediate hepatic elimination of BG (Kalapos‐Kovacs et al, ). Considering the importance of BG, demonstration of a role for OATP2B1 and OATP1B3 in pharmacokinetics of BG using physiologically based pharmacokinetics modeling is warranted.…”

“…Intestinal absorption of BG is limited due to low solubility and there are data showing direct intestinal uptake of BG in the upper segments of small intestine (Lu et al, ). In addition, significant glucuronidation of B occurs in the intestine yielding BG, which is likely effluxed into the mesenteric blood by MRP3 and MRP4 localized in the basolateral membrane of enterocytes (Kalapos‐Kovacs et al, ).…”

San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review

“…Currently, it is verified that Bai from RS is the substrate of both MRP2 and BCRP (Kalapos-Kovács et al, 2015), and another RS constituent Bae is also pumped out by MRP (Zhang et al, 2007). Rhe, Emo and Aem from RR are substrate of BCRP, MRP and P-gp respectively (Wang J. et al, 2011; Liu et al, 2012; Ye et al, 2013), those ITs at least partly reduce the bioavailability of SHXXT constituents by diminishing their intracellular transport.…”