Premium
Pharmacokinetics of four metabolites of DA‐125, a new anthracycline antineoplastic agent after single and multiple intravenous administration to rats
Author(s) -
Lee S. D.,
Lee W. I.,
Shim H. J.,
Lee E. D.,
Kim W. B.,
Yang J.,
Kim C.K.,
Lee M. G.
Publication year - 1996
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/j.1365-2710.1996.tb01140.x
Subject(s) - pharmacokinetics , metabolite , urine , chemistry , excretion , pharmacology , chromatography , medicine , biochemistry
SUMMARY 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 μg min/ml vs. 69.0 μg min/ml), terminal half‐life (t 1/2 : 3.51 h vs. 3.01 h), total body clearance ( CI : 70.9 ml/min/kg vs. 58.0 ml/min/kg), renal clearance ( CI R : 0.193 ml/min/kg vs. 0.336 ml/min/kg) and nonrenal clearance ( CI NR : 70.7 ml/min/kg vs. 57.7 ml/min/kg); of M2, such as plasma AUC (39.4 μg min/ml vs. 41.9 μg min/ml), t 1/2 (6.15 h vs. 7.34 h) and CI R (10.5 ml/min/kg vs. 13.8 ml/min/kg); and of M4, such as plasma AUC (4.82 μg min/ml vs. 6.54 μg min/ml) and t 1/2 (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 MI were 0.326% and 0.694% ( P <0.05). The mean levels of M1 (229 μg vs. 175 μg) and M2 (1330μg vs. 1120μg) 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 AUA , s (area under the amounttime curves from time zero to last measurement time t) (or AUC , s‐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.