Role of P-Glycoprotein in the Intestinal Absorption of Tanshinone IIA, a Major Active Ingredient in the Root of Salvia miltiorrhiza Bunge

Abstract

The extracts from the roots of Salvia miltiorrhiza Bunge (Danshen) are widely and traditionally used in the treatment of angina pectoris, acute myocardial infarct, hyperlipidemia and stroke in China and other Asian countries. In this study, we have investigated the role of P-glycoprotein (P-gp) in the intestinal absorption of tanshinone IIA (TSA), a major active constituent of Danshen, using several in vitro and in vivo models. The oral bioavailability of TSA was about 2.9-3.4% in rats, with non-linear pharmacokinetics when its dosage increased. In a single pass rat intestinal perfusion model, the permeability coefficients (P(app)) based on TSA disappearance from the luminal perfusates (P(lumen)) were 6.2- to 7.2-fold higher (P < 0.01) than those based on drug appearance in mesenteric venous blood (P(blood)). The P(blood), but not P(lumen), was significantly increased when co-perfused with verapamil, or quinidine (both P-gp inhibitors). The uptake and efflux of TSA in confluent Caco-2 cells were significantly altered in the presence of verapamil, quinidine, MK-571, or probenecid. The transport of TSA across Caco-2 monolayers was pH-, temperature- and ATP-dependent. Furthermore, the transport from the apical (AP) to basolateral (BL) side of the Caco-2 monolayers was 3.3- to 8.5-fold lower than that from the BL to AP side, but such a polarized transport was attenuated by co-incubated verapamil or quinidine. A polarized transport was also observed in the control MDCKII cells and more apparent in MDR1-MDCKII monolayers, with the P(app) values of TSA in the BL-AP direction being 7- to 9-fold higher in MDR1-MDCKII monolayers than those in the control MDCKII cells. Moreover, TSA significantly inhibited P-gp-mediated transport of digoxin in P-gp-overexpressing membrane vesicles with an IC(50) of 2.6 microM, but stimulated vanadate-sensitive P-gp ATPase activity with estimated K(m) and V(max) values of 10.70 +/- 0.69 microM and 67.65 +/- 1.31 nmol/min/mg protein, respectively. TSA was extensively metabolized to tanshinone IIB (TSB), and two other oxidative metabolites in rat liver microsomes, but the formation rate of TSB in rat intestinal microsomes was only about 1/10 of that in liver microsomes. These findings indicate that TSA is a substrate and reversing agent for P-gp; and P-gp-mediated efflux of TSA into the gut lumen and the first-pass metabolism contribute to the low oral bioavailability. Further studies are needed to explore the role of other drug transporters and first-pass metabolism in the low bioavailability of TSA.

Tanshinone IIA Exhibits Anticonvulsant Activity in Zebrafish and Mouse Seizure Models

“…17 The complexity of this aforementioned interplay within the larva may contribute to the loss of activity upon 18 h of pre-exposure prior to treatment with PTZ. Other less-active or inactive tanshinones may also play a role in either improving the compounds' penetration into the fish's system by modulating the drug-efflux pumps present in cells 18,19 in a similar fashion to those in bacteria 20 and cancer cells 21 or by modifying the solubilities of the active compounds. 17 Because the lipophilic fraction of danshen has not been fully explored for its potential anticonvulsant effects in earlier literature, the identified active tanshinones bear further analysis, along the lines of structure−activity relationships.…”

Effect of danshen extract on the activity of CYP3A4 in healthy volunteers

“…The poor absorption of tanshinones may have been due to their low aqueous solubility and limited membrane permeability [20]. Yu et al [21] reported that cryptotanshinone is a substrate for P-gp, and that P-gp mediated efflux of cryptotanshinone into the gut lumen. Thus low oral bioavailability was also attributed to the first-pass effect.…”

Tanshinone II-A: new perspectives for old remedies

“…Over the past decade, we [1,[10][11][12][13][14][15][16][17][18][19] and others [20][21][22][23][24] have demonstrated that TSN has potential protective effects against atherosclerosis, cardiac hypertrophy, cardiac fibrosis, diabetes, neurodegenerative diseases, and various kinds of cancers. However, the poor water-solubility, poor intestinal absorption, and low oral bioavailability (about 2.9 --3.4% in rats) [25] have hampered the clinical application of TSN. To overcome these problems, various approaches have been employed, such as the preparation of water-soluble derivative of TSN-sodium tanshinone II-A sulfonate (STS) [4], the preparation of TSN in discoidal and spherical HDL [26], and the development of new drug delivery systems for TSN such as solid dispersion pellets, nanoparticles, and microemulsions [26].…”