Inhibitory effects of nimodipine, nitrendipine and felodipine on tamoxifen metabolism and molecular docking

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 (IC 50 ) values of 5.55 µM, 11.86 µM and 7.71 µM, respectively. In HLM, the IC 50 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.