Predication study on Shexiang Tongxin Dropping Pills-drug interactions mediated by transporter inhibition

Shexiang Tongxin Dropping Pill (STDP), a compound oral preparation of traditional Chinese medicine, has the therapeutic effects of improving myocardial ischemia and relieving chest tightness and pain. It is often used in combination with chemical drugs for cardiovascular diseases in clinical practice. In this paper, the inhibitory effects of STDP on 17 human transporters were studied by cellular accumulation experiments using overexpressing transgenic cell models, including important transporters in the intestine (PEPT1, OATP2B1, MDR1, BCRP), liver (OATP1B1, OATP1B3, OCT1, OAT2), kidney (OAT1, OAT3, OAT4, OCT2, MATE1, MATE2-K), and heart (OCTN1, OCTN2, OCT3). The results showed that STDP inhibited the renal cation transport system (OCT2, MATE1/2-K), but had no significant inhibitory effect on the other 14 transporters. Since the commonly co-administered drugs are not substrates of OCT2 and MATE1/2-K, atenolol and procainamide, the potential co-administered drugs of STDP, were selected as substrates for further study. The results reveled that STDP inhibited the transport of atenolol mediated by MATE1 and MATE2-K, as well as the transport of procainamide mediated by MATE1. Further study showed that the extracts of plasma, liver, and kidney from mice orally administered with STDP, even at 10-folds of clinical dose, merely inhibited MATE1-mediad transport of atenolol by 20%, without inhibiting MATE2-K-meidated transport of atenolol and MATE1/2-K-mediated transport of procainamide. It is speculated that at the clinical dose, STDP is unlikely to significantly affect the renal excretion of the two drugs. The above results suggest that at the clinical dose, STDP is unlikely to induce significant drug-drug interactions (DDIs) due to the inhibition of the above transporters. The animal experiments have been approved by the Animal Ethics Committee of Zhejiang University (approval number: ZJU20230086).