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) (2670 vs 5700 ml kg(-1)) were 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) (28500 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. administration 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 degrees C and at a rate of 300 rpm.