1.Differential effects of the optical isomers of KR30031 on cardiotoxicity and on multidrug resistance reversal activity.
Lee BH1, Lee CO, Kwon MJ, Yi KY, Yoo SE, Choi SU. Anticancer Drugs. 2003 Feb;14(2):175-81.
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 microM, 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.
2.Enhanced oral bioavailability of paclitaxel by coadministration of the P-glycoprotein inhibitor KR30031.
Woo JS1, Lee CH, Shim CK, Hwang SJ. Pharm Res. 2003 Jan;20(1):24-30.
PURPOSE: In an attempt to improve the oral bioavailability of paclitaxel, a novel P-glycoprotein inhibitor, KR30031, which is verapamil analog with fewer cardiovascular effects, was coadministered with paclitaxel, and to elucidate other possible causes of the low oral bioavailability of paclitaxel, an inhibitor of hepatic metabolism, ketoconazole, was also coadministered with paclitaxel.