Role of the ATP-binding cassette drug transporters in the intestinal absorption of tanshinone IIB, one of the major active diterpenoids from the root of Salvia miltiorrhiza

There is an increasing use of herbal medicines worldwide, and the extracts from the root of <i>Salvia miltiorrhiza</i> are widely used in the treatment of angina and stroke. In this study, we investigated the mechanism for the intestinal absorption of tanshinone IIB (TSB), a major constituent of <i>S. miltiorrhiza</i>. The oral bioavailability of TSB was about 3% in rats with less proportional increase in its maximum plasma concentration (<i>C</i>_max) and area under the plasma concentration-time curve (AUC) with increasing dosage. The time to <i>C</i>_max(<i>T</i>_max) was prolonged at higher oral dosage. In a single pass rat intestinal perfusion model, the permeability coefficients (<i>P</i>_app) based on TSB disappearance from the lumen (<i>P</i>_lumen) were 6.2- to 7.2-fold higher (<i>p</i> < 0.01) than those based on drug appearance in mesenteric venous blood (<i>P</i>_blood). The uptake and efflux of TSB in Caco-2 cells were also significantly altered in the presence of an inhibitor for P-glycoprotein (PgP) or for multi-drug resistance associated protein (MRP1/2). TSB transport from the apical (AP) to basolateral (BL) side in Caco-2 monolayers was 3.3- to 5.7-fold lower than that from BL to AP side, but this polarized transport was attenuated by co-incubation of PgP or MRP1/2 inhibitors. The <i>P</i>_appvalues of TSB in the BL-AP direction were significantly higher in MDCKII cells over-expressing MDR1 or MRP1, but not in cells over-expressing MRP2-5, as compared with the wild-type cells. The plasma AUC_0-24hr in <i>mdr</i>1<i>a</i> and <i>mrp</i>1 gene-deficient mice was 10.2- to 1.7-fold higher than that in the wild-type mice. Furthermore, TSB significantly inhibited the uptake of digoxin and vinblastine in membrane vesicles containing PgP or MRP1. TSB also moderately stimulated PgP ATPase activity. Taken collectively, our findings indicate that TSB is a substrate for PgP and MRP1 and that drug resistance to TSB therapy and drug interactions may occur through PgP and MRP1 modulation.<br />