Carvedilol Phosphate

Tamoxifen, a selective estrogen receptor modulator (SERM) used in breast cancer therapy, requires metabolic activation by CYP3A4 to exert its biological effects. This study evaluated the effects of calcium channel blockers nimodipine, nitrendipine and felodipine on tamoxifen metabolism by studying their interactions with tamoxifen in vitro and in vivo. Rat liver microsomes (RLM) and human liver microsomes (HLM) were used in this study to evaluate the inhibitory potential of nimodipine, nitrendipine and felodipine on tamoxifen metabolism in vitro. A total of 28 cardiovascular drugs, including calcium channel blockers, were screened in an RLM incubation system in vitro. In RLM, nimodipine, nitrendipine and felodipine had half-maximum inhibitory concentration (IC₅₀) values of 5.55 µM, 11.86 µM and 7.71 µM, respectively. In HLM, the IC₅₀ values were increased to 20.38 µM, 30.06 µM, and 44.45 µM for nimodipine, nitrendipine and felodipine, respectively. The kinetic assays indicated that nimodipine and felodipine inhibited the metabolism of tamoxifen in a competitive way, whereas nitrendipine showed non-competitive inhibition in RLM. However, felodipine exhibited non-competitive inhibition, and nimodipine and nitrendipine showed competitive inhibition in HLM. Pharmacokinetic studies in rats revealed that pretreatment with nimodipine and nitrendipine significantly increased the systemic exposure of tamoxifen, as demonstrated by increasing the area under the curve (AUC), the maximum concentration (C_max) and decreasing the clearance (CL_z/F). Finally, molecular docking studies supported these findings, showing potential interactions at the active site of CYP3A4. These results suggested the necessity for careful monitoring and possible dose adjustments of tamoxifen when co-administered with calcium channel blockers in clinic.

Cisplatin is a common chemotherapy agent for solid tumors but severe nephrotoxicity limits its application, with no effective pharmacological treatments. Organic cation transporter 2 (OCT2) is involved in cisplatin uptake in kidneys. This study aimed to find drugs with promising clinical applications that could prevent cisplatin-induced acute kidney injury (Cis-AKI) by inhibiting OCT2.

The mRNA level of OCT2 was examined in human induced pluripotent stem cells (iPSCs) from Cis-AKI patients and paired non-AKI patients. The association between OCT2 and Cis-AKI was investigated by HEK293FT cells and kidney organoids. We screened potential compounds exhibiting protective effects against Cis-AKI in US Food and Drug Administration-approved drugs through virtual screening and activity screening. Subsequently, we determined the effects of these compounds on OCT2 expression, cisplatin uptake, and apoptosis in cells, kidney organoids and mice. A549 and HeLa cells were adopted to observe the influence of drugs on the anti-tumor function of cisplatin.

Compared to non-AKI patients, the OCT2 mRNA levels of iPSCs from Cis-AKI patients were elevated. OCT2 exhibits similar expression patterns in kidney organoids and human kidney tissues. Furthermore, the overexpression of OCT2 in kidney organoids and HEK293FT cells exacerbated the injury caused by cisplatin. Carvedilol and cimetidine were identified as potent OCT2 inhibitors by drug screening. Further analysis revealed that the pretreatment of carvedilol or cimetidine downregulated OCT2, reduced cisplatin uptake, and alleviated cisplatin-induced apoptosis, but the combination of the two drugs didn't further improve these outcomes. Additionally, carvedilol and cimetidine didn't compromise the cisplatin-induced cell death in A549 and HeLa cells.

Our study confirmed that carvedilol and cimetidine exert protective effects against Cis-AKI by inhibiting OCT2, without altering the anti-tumor effects of cisplatin.