Pharmacokinetics of four metabolites of DA-125, a new anthracycline antineoplastic agent after single and multiple intravenous administration to rats.

Abstract

The tissue distribution, and biliary and urinary excretion of four metabolites (M1-M4) of a new anthracycline antineoplastic agent (DA-125) were compared after single and multiple (7 consecutive days) intravenous (i.v.) administration to rats. The mean pharmacokinetic parameters of M1, such as area under the plasma concentration-time curve (AUC: 56.4 micrograms/ml vs. 69.0 micrograms min/ml), terminal half-life (t1/2: 3.51 h vs. 3.01 h), total body clearance (Cl: 70.9 ml/min/kg vs. 58.0 ml/min/kg), renal clearance (ClR: 0.193 ml/min/kg vs. 0.336 ml/min/kg) and nonrenal clearance (ClNR: 70.7 ml/min/kg vs. 57.7 ml/min/kg); of M2, such as plasma AUC (39.4 micrograms min/ml vs. 41.9 micrograms min/ ml), t1/2 (6.15 h vs. 7.34 h) and ClR (10.5 ml/min/ kg vs. 13.8 ml/min/kg); and of M4, such as plasma AUC (4.82 micrograms min/ml vs. 6.54 micrograms min/ml) and t1/2 (3.33 h vs 4.02 h), were comparable between single and multiple administrations of DA-125. M3 was detected in plasma for up to 1-5 min, and M3 and M4 were below the detection limit in 24-h urine after both single and multiple administrations of DA-125. M2 was the main metabolite of DA-125 excreted (among M1-M4) in 24-h urine after both single and multiple administrations of DA-125; approximately 12.3% and 20.1% (P < 0.01) of i.v. dosage (expressed in terms of DA-125) was excreted as M2 after single and multiple administrations of DA-125, respectively. Corresponding values for M1 were 0.326% and 0.694% (P < 0.05). The mean levels of M1 (229 micrograms vs. 175 micrograms) and M2 (1330 micrograms vs. 1120 micrograms) excreted in 24-h bile after single and multiple administrations of DA-125 were not significantly different; the percentages of i.v. dosage excreted in 24-h bile as M1 (expressed in terms of DA-125) were 4.83% and 3.58% after single and multiple administrations, respectively. The corresponding values for M2 were 27.8% and 22.5%. M3 and M4 were below the detection limit in 24-h bile after both single and multiple administrations of DA-125. Mean AUAts (area under the amount-time curves from time zero to last measurement time t) (or AUCts-area under the plasma concentration-time curves from time zero until the last measurement time t) of M1-M4 in each tissue after single and multiple administrations of DA-125 were also comparable except in the bone marrow and thymus. The data suggest that 7 consecutive days of i.v. administration of DA-125 (4 mg/kg) to rats does not lead to considerable accumulation of M1-M4 in the tissues, except in the bone marrow and thymus.