MK-571

The low oral bioavailability of puerarin (Pue) affects its therapeutic effect. The aim of this study is to enhance the absorption of Pue and improve therapeutic efficacy by adding cinnamaldehyde (CA). The pharmacokinetics of Pue in rats were studied using oral administration: CA + Pue, and single Pue. The Caco-2 cell model was used to investigate the effect of CA on the absorption and transport of Pue. The absorption sensitivity of TSG to P-gp inhibitors verapamil (Ver), Ko143, and MK-571 in vivo were simultaneously evaluated, and assessed the effects of ATP binding cassette (ABC) transporter inhibitors (such as P-gp inhibitors verapamil, MK-571, and BCRP inhibitor Ko143) on predicting targeted transport of active ingredients to explore the relationship between Pue transport and inhibition of these efflux proteins. A rat model of middle cerebral artery occlusion (MCAO) was established to explore the therapeutic effect of single Pue and Pue with CA on ischemic stroke (IS). The results showed that compared with Pue suspension, CA increased the absorption of Pue in rats, with C_max and AUC_(0-t) being 4.84 times and 11.54 times higher, respectively. Both P-gp and MRP play a role in the transport mechanism of Pue. Compared with single Pue, the transmembrane transport from Basolateral (BL) to Apical (AP) side of Pue was significantly reduced when Pue was applied in combination with CA. In addition, the efflux ratio (ER) value also significantly decreased. This discovery suggests that CA may reduce the secretion of Pue, thereby enhancing its absorption and transport by inhibiting exocytosis mediated by efflux transporters, similar to the effect of Ver. On the other hand, in the MCAO rat model, Pue + CA reduced the extent of cerebral infarction, alleviated pathological damage, significantly reduced the level of inflammatory mediators, and increased the release of anti-inflammatory factors, suggesting that CA can synergize with Pue to exert a better therapeutic effect on IS. Therefore, the combination of Pue and CA for the treatment of IS has profound scientific significance and rationality from the points of disposition and pharmacodynamics in vivo.