Comparison of pharmacokinetics of M1, M2, M3, and M4 after intravenous administration of DA-125 or ME2303 to mice and rats. New adriamycin analogues containing fluorine.

The pharmacokinetics of M1, M2, M3 and/or M4 were compared after intravenous (i.v.) administration of DA-125 and/or ME2303 to mice (25 mg kg(-1)) and rats (5, 10, 20, 30, and 40 mg kg(-1)). The mean plasma concentrations of M1 were detected up to 8 h after i.v. administration of both DA-125 and ME2303 to mice, and were significantly higher for DA-125 than ME2303; this resulted in a considerably greater AUC (303 against 148 micrograms min mL(-1)) and a considerably slower CL of M1 (69.3 against 136 mL min-1 kg(-1)) after i.v. administration of DA-125. The MRT (371 against 189 min) and CLNR of M1 (68.7 against 136 mL min-1 kg(-1)) were considerably greater and slower, respectively, after i.v. administration of DA-125. The mean plasma concentrations of M2 were detected up to 8 and 4 h after i.v. administration of DA-125 and ME2303, respectively, to mice and were significantly higher for DA-125 than ME2303, resulting in a considerably greater AUC of M2 (148 against 27.1 micrograms min mL(-1)) after i.v. administration of DA-125. The mean plasma concentrations of M3, being the lowest among M1-M4, were detected only up to 15 min after i.v. administration of both DA-125 and ME2303 to mice, and were comparable after i.v. administration of DA-125 and ME2303 to mice. The mean plasma concentrations of M4 were detected up to 8 h after i.v. administration of both DA-125 and ME2303 to mice, and were higher after i.v. administration of DA-125 than ME2303, resulting in a considerably greater AUC of M4 (197 against 61.9 micrograms min mL(-1)) after i.v. administration of DA-125. Similar results on M1 and M2 were also obtained from rats: the mean plasma concentrations of both M1 and M2 were significantly higher after i.v. administration of DA-125, 10 mg kg(-1), than after ME2303. The plasma concentrations of M1, M2, and M4, and hence their AUCs, were significantly higher after i.v. administration of DA-125, 5, 10, 20, 30, and 40 mg kg(-1), to rats than after ME2303: the mean plasma concentrations of M2, approximately 0.1-0.4 micrograms mL(-1), were maintained from 30 min to 8-10 h after i.v. administration of DA-125, 20, 30, and 40 mg kg(-1), to rats; the plasma concentrations of M3 were the lowest among M1-M4 at all DA-125 doses; and those of M1 and M4 were maintained for a long period of time. However, after i.v. administration of M2, 5 mg kg(-1), to rats, the mean plasma concentrations of M2 were detected up to 60 min with a mean terminal half-life of only 38.8 min, and the concentrations of M3 were negligible. After i.v. administration of M3, 5 mg kg(-1), to rats, the mean plasma concentrations of M3 were detected up to 15 min; the plasma concentrations of M4, reaching their peak at 5 min, decayed more slowly and were higher than those of M3. The AUC of M4 after i.v. administration of M3, 5 mg kg(-1), was comparable to that after i.v. administration of M4, 5 mg kg(-1), to rats, suggesting that M4 is formed fast and almost completely from M3. M1 was not detected in plasma after i.v. administration of either M2 or M3 to rats. After i.v. administration of M4, 5 mg kg(-1), to rats, the mean plasma concentrations of M4 decayed fast with a mean terminal half-life of 43.9 min and neither M2 nor M3 were detected in plasma. The following disposition mechanisms for M1, M2, M3, and M4 after i.v. administration of DA-125 to rats could be obtained from the above data; (i) the maintenance of plasma concentrations of M2 for a longer period of time after i.v. administration of DA-125 than those after i.v. administration of M2 could be due to the continuous formation of M2 from M1; (ii) the lowest plasma concentrations of M3 among M1-M4 after i.v. administration of DA-125 could be due to the fast and almost complete information of M4 from M3 as soon as M3 is formed from M1, and not due to the fast renal excretion of unchanged M3; (iii) M4 was exclusively and continuously formed from M3 and the formation of M4 from M2 was negligible; and (i.v.) reversible me