Effects of dexamethasone on the pharmacokinetics of adriamycin after intravenous administration to rats.
Adriamycin was metabolized to adriamycinol by the cytoplasmic aldo-keto reductase and adriamycin and adriamycinol were further metabolized to their deglycosylated aglycones, M3 and M4, respectively, by cytochrome P450. SKF-525A (a cytochrome P450 inhibitor) and dexamethasone (a cytochrome P450 inducer) were pretreated to rats. Adriamycin, 16 mg/kg, was infused over 1-min via the jugular vein of each rat. After pretreatment with SKF-525A, the area under the plasma concentration-time curve of adriamycin from time zero to the last measured time in plasma, 8 h (537 versus 155 microg x min/ml) was significantly greater, and the 24-h urinary excretion of M3 (1.65 versus 23.8 microg), and M3, M4, and their glucuronide and/or sulfate conjugates (33.7 versus 3.38 microg) were significantly smaller than those in control rats suggesting that the formation of M3 and M4 were inhibited by SKF-525A. After pretreatment with dexamethasone, the 24-h urinary excretion of M3 (94.5 versus 23.8 microg), M4 (8.43 versus 2.78 microg), and M3, M4, and their glucuronide and/or sulfate conjugates (116 versus 33.7 microg) were significantly greater than those in control rats, suggesting that the formation of M3 and M4 seemed to be induced by dexamethasone.
Lee
H J
HJ
College of Pharmacy, Seoul National University, Kwanak-Gu, South Korea.
Lee
M G
MG
D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D003907:Dexamethasone; D004317:Doxorubicin; D011335:Proadifen