Dose-dependent pharmacokinetics of flavone acetic acid in mice.
The pharmacokinetics of the novel anticancer agent, flavone acetic acid (FAA) were investigated in Balb-c mice treated with i.v. doses of 100 mg/kg or 300 mg/kg, using an HPLC assay. The kinetics of disappearance from plasma was monoexponential and dose-dependent. After 100 mg/kg, the plasma peak level was 250 +/- 11 micrograms/ml, t1/2 was 0.5 h, and AUC was 309 micrograms/ml per h. After 300 mg/kg, the plasma peak level was 710 +/- 57 micrograms/ml, t1/2 was 2.1 h, and the area under the curve (AUC) 1771 micrograms/ml h. Mouse plasma protein binding of FAA was about 70%. As is the case with plasma, in all tissues analyzed, the FAA-AUC values were disproportinately greater after 300 mg/kg than after 100 mg/kg. The highest drug concentrations were found in the liver and small intestine; concentrations were intermediate in lung, heart, and spleen, and lowest in brain. Less than 5% of the FAA dose was eliminated as unchanged drug in the stool. Total excretion of FAA as unchanged drug in the urine collected up to 96 h after drug treatment corresponded to 75% and 60% of the i.v. doses of 100 and 300 mg/kg, respectively. A minor fraction of FAA dose, corresponding to 1% and 6% of the two doses, was eliminated in the urine as a FAA glucuronide or sulfate.
Damia
G
G
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Zanette
M L
ML
Rossi
C
C
Mandelli
R
R
Ferrari
A
A
D'Incalci
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D005419:Flavonoids; C049328:flavone acetic acid