Pharmacokinetic changes of M1, M2, M3, and M4 after intravenous administration of a new anthracycline, DA-125, to alloxan-induced diabetes mellitus rats.
The pharmacokinetics of M1, M2, M3, and M4 were compared after intravenous (i.v.) administration of DA-125, 15 mg/kg to the control (n = 15) and alloxan-induced diabetes mellitus (AIDM, n = 11) rats. After i.v. administration of DA-125, almost 'constant' plasma concentrations of M1 and M2 were maintained from 1-2 h onwards to 8-10 h in both groups of rats due to the continuous formation of M2 from M1. The plasma concentrations of M3 were the lowest among M1-M4 in the control rats due to the rapid and essentially complete conversion of M3 to M4. The AUC0-8 h of M1 (189 versus 78.5 mg min/ml) was significantly greater in the AIDM rats than that in the control rats. However, the AUCts of M2 (32.7 versus 44.3 micrograms min/ml) and M4 (not measurable versus 19.7 micrograms min/ml) were significantly smaller in the AIDM rats. The renal clearances of both M1 (0.157 versus 0.334 ml/min/kg) and M2 (0.726 versus 14.6 ml/min/kg) decreased significantly in the AIDM rats, presumably due to their impaired kidney function. The liver weight decreased significantly in the AIDM rats (2.77 versus 3.77% of body weight), suggesting impaired liver function. Above data suggested that the metabolism of M1 to M2-M4 in the liver and kidney decreased significantly in the AIDM rats. M2 was the main metabolite among M1-M4 excreted in 24 h urine in both group of rats. In the AIDM rats, the amount of M2 excreted in 24 h urine decreased significantly (15.7 versus 229 micrograms) whereas the amount of M2 recovered at 24 h from the whole GI tract increased significantly (45.1 versus 14.0 micrograms).
Choi
Y J
YJ
College of Pharmacy, Seoul National University, Korea.
Lee
H J
HJ
Kwon
J W
JW
Kim
W B
WB
Yang
J
J
Lee
M G
MG
D000496:Alloxan; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006207:Half-Life; D007668:Kidney / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D001786:Blood Glucose; C090816:7-O-(2,6-Dideoxy-2-fluoro-alpha-talopyranosyl)adriamycinone- 14-beta-alaniate hydrochloride; D000496:Alloxan; D004317:Doxorubicin