Differential effects of the optical isomers of KR30031 on cardiotoxicity and on multidrug resistance reversal activity

The present study was performed to compare the cardiovascular adverse effects of verapamil, KR30031 and their optical isomers, and also to measure their ability to overcome multidrug resistance (MDR). The R-isomer of KR30031 (R-KR30031) was equipotent with the S-isomer of KR30031 (S-KR30031) and 25-fold less potent than the R-isomer of verapamil (R-verapamil) in relaxing the aorta isolated from rat (EC50: 11.8,10.2 and 0.46 muM, respectively). The effect of R-KR30031 in decreasing left ventricular pressure of heart isolated from rat was 2- and 267-fold smaller than those of S-KR30031 and R-verapamil, respectively (EC50: 23.9, 9.4 and 0.089 mM, respectively). The hypotensive effect of R-KR30031 in rat was about 2- and 23-fold smaller than those of S-KR30031 and R-verapamil, respectively (ED20: 1.15, 0.60 and 0.05 mg/kg, respectively). On the other hand, R-KR30031 elicited potency similar to those of S-KR30031 and R-verapamil in enhancing the paclitaxel-induced cytotoxicity to HCT15/ CL02 and MES-SA/DX5 cells that reveal high levels of P-glycoprotein expression (IC50: 3.11, 3.04 and 2.58 muM, respectively). In addition, the intrinsic cytotoxicity of R-KR30031 in HCT15/CLO2 and M ES-SA/DX5 cells was observed only at the very high concentration of 100 muM. All these results suggest that R- and racemic KR30031 are active modulators of MDR with potentially minimal cardiovascular adverse activity. Anti-Cancer Drugs 14:175-181 (C) 2003 Lippincott Williams Wilkins.