PHARMACOKINETICS AND ANTITUMOR-ACTIVITY OF A NEW PLATINUM COMPOUND, CIS-MALONATO[(4R,5R) 4,5-BIS(AMINOMETHYL)-2-ISOPROPYL-1, 3-DIOXOLANE]PRATINUM(II), AS DETERMINED BY EX-VIVO PHARMACODYNAMICS

The pharmacokinetics and ex vivo pharmacodynamics studies on cis-malon ato [(4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1, 3-dioxolane]platinum (II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDC A) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma sam ples were analyzed for platinum by flameless atomic absorption spectro photometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean are a under the concentration time curve (AUC(0-->infinity)) determined fo r ultrafiltrable platinum derived from SKI 2053R, as an active compone nt, was 7.72 +/- 2.74 mu g h ml(-1) (mean +/- SD), with an initial hal f-life of 0.37 +/- 0.20 h, a terminal half-life of 2.19 +/- 0.93 h, a total clearance of 16.83 +/- 4.76 ml min(-1)kg(-1), and a steady-state volume of distribution of 1.57+/-0.30 l/kg. The ex vivo antitumor act ivity of SKI 2053R was assessed using the ultrafiltrable plasma agains t two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five s tomach-adenocarcinoma cell lines (MKN-45, KATO III: SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of C DDP and CBDCA using an antitumor index (ATI) determined from the ex vi vo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P < 0.05) higher than that noted for CDDP; h owever, no statistically significant difference was observed between S KI2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further d evelopment as a clinically useful anticancer drug.