Pharmacokinetics of FT-ADM after intravenous administration of DA-125, a prodrug of FT-ADM or FT-ADM to rats. A new adriamycin analog containing fluorine

The pharmacokinetics of DA-125 or its active metabolite, M1 (FT-ADM), an adriamycin analog containing fluorine were compared after intravenous (i.v.) administration of DA-125 or M1 in rats. DA-125, 20 mg kg^-1 was dissolved in 1 mM lactic acid/0.9% NaCl solution (treatment I) or 100% dimethylsulfoxide (DMSO, treatment II), and M1, 20 mg kg was dissolved in 100% DMSO (treatment III) due to its poor water solubility. The plasma concentrations of DA-125 and M1, and the pharmacokinetic parameters of DA-125, such as terminal half-life (t _{1 2}, 1.64 vs 2.07 min), mean residence time (MRT, 1.52 vs 2.60 min), total body clearance (CL, 165 vs 186 ml min^-1 kg^-1) and apparent volume of distribution at steady state (Vd_ss, 254 vs 411 ml kg^-1), and of M1 (based on plasma data up to 1 h), such as (t _{1 2} (30.2 vs 38.7 min), MRT (19.1 vs 31.6 min), CL (187 vs 189 ml min^-1 kg^-1) and Vd_ss(2670vs 5700 ml kg^-1were similar between treatments I and II, indicating that the effect of 100% DMSO on the pharmacokinetics of DA-125 or M1 seemed to be negligible, if any. The plasma concentrations of M1, and the pharmacokinetic parameters of M1 (based on plasma data up to 8 h when the dose of M1, 20 mg kg^-1 was normalized to the dose of DA-125, 20 mg kg^-1), such as (t _{1 2} (255 vs 221 min), MRT (269 vs 235 min), CL (103 vs 112 ml min^-1 kg^-1) and Vd_ss (28 500 vs 26300 ml kg^-1) were also similar between treatments II and III. The above results indicate that DA-125 is rapidly hydrolyzed to M1 after i.v. administration of DA-125. Therefore, the estimation of the pharmacokinetic parameters of M1 after i.v. administra- tion of DA-125 appeared not to cause any differences, if any when compared with the values after i.v. dose of M1. The rapid hydrolysis of DA-125 to M1 was demonstrated during an in vitro study; the (t _{1 2} values of hydrolysis of DA-125 were 1.97, 1.72, 0.54 and 0.54 min in the plasma from mouse, rat, dog and human, respectively, when the plasma containing DA-125 was incubated in a shaking water bath kept at 37°C and at a rate of 300 rpm.