Serum concentrations of amiodarone required for an in vivo modulation of anthracycline resistance.
We demonstrated previously that amiodarone is able to circumvent in vitro the inherent resistance to anthracyclines of the DHD/K12 rat colon cancer cell line. We have now determined in the rat the amiodarone seric concentrations required to enhance the in vitro cytotoxicity of 4'-deoxydoxorubicin (deoDX) against DHD/K12 cells. A maximal deoDX potentiation was obtained in vitro when anthracycline was diluted in the serum of rats receiving at least 75 mg/kg of intravenous amiodarone resulting in seric concentrations of more than 40 micrograms/ml. In patients treated with amiodarone, the mean serum concentrations were 0.9 +/- 0.1 microgram/ml after an one month's oral administration of 200 mg/day, 2.2 +/- 1.0 micrograms/ml after a 24 hr continuous infusion of 300 to 900 mg/day and 5.4 +/- 1.1 micrograms/ml after a brief 3 hrs infusion of 450 mg amiodarone. Such amiodarone concentrations in human serum are much lower than those necessary to produce a significant anthracycline potentiation. In rats receiving amiodarone at a maximal tolerated dose (100 mg/kg) minutes before the injection of 10 mg/kg doxorubicin (DX), we observed an increased accumulation of the anthracycline in the liver and kidney compared to rats receiving DX alone. The DX content was not modified by amiodarone in the other organs studied (heart, lung, spleen and pancreas). An amiodarone pretreatment accelerated the death of rats receiving 5 or 10 mg/kg DX did not provoke lethality for a lower dose of 2.5 mg/kg DX. The very high doses required and the risk of increased toxicity seem to preclude the use of amiodarone for the modulation of anthracycline resistance in cancer patients.
Genne
P
P
Inserm U. 252, Faculty of Medicine, Dijon, France.
Coudert
B
B
Pelletier
H
H
Girardot
C
C
Martin
F
F
Chauffert
B
B
D000277:Adjuvants, Pharmaceutic / Q000493:pharmacokinetics / Q000627:therapeutic use; D000638:Amiodarone / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004351:Drug Resistance; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D000277:Adjuvants, Pharmaceutic; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D000638:Amiodarone; C030851:esorubicin