Potential Involvement of Organic Anion Transporters in Drug Interactions with Shuganning Injection, a Traditional Chinese Patent Medicine.

Traditional Chinese medicine injections have been widely used in China for the treatment of various diseases. Transporter-mediated drug-drug interactions are a major contributor to adverse drug reactions. However, the research on transporter-mediated Traditional Chinese medicine injection-drug interactions is limited. Shuganning injection is a widely used Traditional Chinese medicine injection for treating various liver diseases. In this study, we investigated the inhibitory effect of Shuganning injection and its four main ingredients (baicalin, geniposide, chlorogenic acid, and oroxylin A) on 9 drug transporters. Shuganning injection strongly inhibited organic anion transporter 1 and organic anion transporter 3 with IC50 values < 0.1% (v/v), and moderately inhibited organic anion transporter 2, organic anion transporting-polypeptide 1B1, and organic anion transporting-polypeptide 1B3 with IC50 values < 1.0%. Baicalin, the most abundant bioactive ingredient in the Shuganning injection, was identified as both an inhibitor and substrate of organic anion transporter 1, organic anion transporter 3, and organic anion transporting-polypeptide 1B3. Oroxylin A had the potential to act as both an inhibitor and substrate of organic anion transporting-polypeptide 1B1 and organic anion transporting-polypeptide 1B3. In contrast, geniposide and chlorogenic acid had no significant inhibitory effect on drug transporters. Notably, Shuganning injection markedly altered the pharmacokinetics of furosemide and atorvastatin in rats. Using Shuganning injection as an example, our findings support the implementation of transporter-mediated Traditional Chinese medicine injection-drug interactions in the development of Traditional Chinese medicine injection standards.

Cytochrome P450-mediated herb-drug interaction (HDI) of Polygonum multiflorum Thunb. based on pharmacokinetic studies and in vitro inhibition assays.

BACKGROUND: Polygonum multiflorum Thunb. (PM) is well known both in China and other countries of the world for its tonic properties, however, it has lost its former glory due to liver toxicity incidents in recent years. PURPOSE: The purpose of this study is to determine whether the occurrence of herb-drug interaction (HDI) caused by PM is associated with cytochrome P450 (CYP450) based on pharmacokinetic studies and in vitro inhibition assays. The objective was to provide a reference for the rational and safe use of drugs in clinical practice. METHODS: In this study, raw PM (R), together with its two processed products which included PM by Chinese Pharmacopoeia (M) and PM by "nine cycles of steaming and sunning (NCSS)" ("9"), were prepared as the main research objects. A method based on fluorescence technology was used to evaluate the inhibition levels of raw and processed PMs, as well as corresponding characteristic compounds on seven recombinant human cytochrome P450s (rhCYP450s). The pharmacokinetics of sulindac (a representative of commonly used nonsteroidal anti-inflammatory drugs) and psoralen (a major compound of Psoralea in combination with PM) in rat plasma were studied when combined with raw and different processed products of PM. RESULTS: The inhibitory level order of the three extracts on major different subtypes of CYP450 (CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP3A4) was: R > M > "9". However, the inhibition level of R and "9" is higher than that of M on CYP2C9. Further studies showed that trans-THSG and emodin could selectively inhibit CYP3A4 and CYP1A2, respectively. Epicatechin gallate mainly inhibited CYP3A4 and CYP1A2, followed by CYP2C8 and CYP2C9. Genistein mainly inhibited CYP3A4, followed by CYP2C9 and CYP2C8. CYP3A4 and CYP2C9 were also inhibited by daidzein. The inhibitory effects of all the PM extracts were associated with their characteristic compounds. The results of HDI showed that R increased sulindac exposure to rat blood, and R and M increased psoralen exposure to rat blood, which were consistent with corresponding metabolic enzymes. Overall, the in vitro and in vivo results indicated that PM, especially R, would be at high risk to cause toxicity and drug interactions via CYP450 inhibition. CONCLUSION: This study not only elucidates the scientific connotation of "efficiency enhancement and toxicity reduction" of PM by NCSS from the perspective of metabolic inhibition but also contributes to HDI prediction and appropriate clinical medication of PM.

Transporter-mediated Natural Product-Drug Interactions.

The increasing use of natural products in clinical practice has raised great concerns about the potential natural product-drug interactions (NDIs). Drug transporters mediate the transmembrane passage of a broad range of drugs, and thus are important determinants for drug pharmacokinetics and pharmacodynamics. Generally, transporters can be divided into ATP binding cassette (ABC) family and solute carrier (SLC) family. Numerous natural products have been identified as inhibitors, substrates, inducers, and/or activators of drug transporters. This review article aims to provide a comprehensive summary of the recent progress on the research of NDIs, focusing on the main drug transporters, such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter 1 and 3 (OAT1/OAT3), organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1/OATP1B3), organic cation transporter 2 (OCT2), multidrug and toxin extrusion protein 1 and 2-K (MATE1/MATE2-K). Additionally, the challenges and strategies of studying NDIs are also discussed.

Wedelolactone protects against cisplatin-induced nephrotoxicity in mice via inhibition of organic cation transporter 2.

The balance of cisplatin uptake and efflux, mediated mainly by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1), respectively, determines the renal accumulation and nephrotoxicity of cisplatin. Using transporter-mediated cellular uptake assay, we identified wedelolactone (WEL), a medicinal plant-derived natural compound, is a competitive inhibitor of OCT2 and a noncompetitive inhibitor of MATE1. Wedelolactone showed a selectivity to inhibit OCT2 rather than MATE1. Cytotoxicity studies revealed that wedelolactone alleviated cisplatin-induced cytotoxicity in OCT2-overexpressing HEK293 cells, whereas it did not alter the cytotoxicity of cisplatin in various cancer cell lines. Additionally, wedelolactone altered cisplatin pharmacokinetics, reduced kidney accumulation of cisplatin, and ameliorated cisplatin-induced acute kidney injury in the Institute of Cancer Research mice. In conclusion, these findings suggest a translational potential of WEL as a natural therapy for preventing cisplatin-induced nephrotoxicity and highlight the need for drug-drug interaction investigations of WEL with other treatments which are substrates of OCT2 and/or MATE1.