Pharmacokinetic Investigation on a Novel Antitumour Platinum Compound in Rabbit Plasma by Inductively Coupled Plasma Mass Spectrometry After Intravenous Administration

Abstract

The purpose of this study was to investigate a novel platinum anticancer compound named as SM54111 [cis-3, 5-diisopropylsalylic cyclohexanodiaminoplatinum (II)], which is under development as a new drug candidate, on its pharmacokinetics in plasma after intravenous administration to rabbits at concentration of 2.5, 5.0, and 9.0 mg/kg. The concentration of SM54111 in plasma expressed as Pt was determined utilizing ICP-MS method, and the method was thoroughly validated. The data were analyzed with 3P97 pharmacokinetic software to find the parameters. The results showed that the linear range lay at the 1 ∼1000 ng/mL level, and the LOD and LOQ were 0.4 ng/mL and 1 ng/mL, respectively. It proved that this new drug candidate underwent disposition in rabbit plasma by a two-compartment open model at the three doses above, and the main pharmacokinetic parameters were obtained as the initial concentrations of three doses (C₀) were 8.68 ± 0.80, 20.04 ± 1.92, and 28.88 ± 2.32 mg/L, respectively; the areas under concentration-time profile from time 0 to 72 h (AUC_0∼t) were 90.0 ± 13.0, 251.3 ± 45.3, and 396.9 ± 61.1 mg*h/L, respectively; the terminal elimination half-life times (t_1/2β) 29.1 ± 4.8, 35.2 ± 7.5, and 29.4 ± 2.8 h, respectively; and the total clearances (CL_tot) were 0.026 ± 0.004, 0.019 ± 0.002, and 0.022 ± 0.004 L/h, respectively. First order rate pharmacokinetics were observed for SM54111 with the doses used, and it showed a long retention and slow elimination in vivo, There showed no prolongation of the t_1/2β with larger dose, and the CLs of the three doses were proximate. It is reasonable to surmise that SM54111 follows first order rate pharmacokinetics, and no saturation was detected at concentrations from 2.5 to 9.0 mg/kg. This result suggested that SM54111 experienced an amiable procedure in vivo and was worthy of the further development.

Keywords:

• SM54111
• pharmacokinetics
• platinumcomplex
• anticancer
• ICP-MS