Hepatic extraction, metabolism and biliary excretion of doxorubicin in the isolated perfused rat liver.
The hepatic extraction, metabolism, and biliary excretion of doxorubicin (DX) were studied in the isolated perfused rat liver. Three doses of DX equivalent to 2, 20, and 100 mg/kg in rats were studied over a period of 3 h after bolus injection into the reservoir. DX and metabolites concentration in perfusate, bile, and liver were determined by high-pressure liquid chromatography. The hepatic extraction ratio was low (less than 0.24) and decreased progressively over the 3 h. The hepatic extraction and clearance were significantly lower at the highest dose. Doxorubicinol (DX-OL) was the only metabolite detected in the perfusate, accounting for less than 4% of the total AUC. Thirty-one to thirty-three percent of the dose was excreted into bile over 3 h as unchanged DX. This was reduced to 22% at the highest dose. Only 0.35%-1.33% of the dose was excreted as DX-OL. DX aglycones were found only in the liver, where they represented 20%-30% of the total fluorescence at 3 h. In conclusion, in this model DX has a low extraction ratio, is poorly metabolized and extensively excreted into bile.
D000818:Animals; D001646:Bile / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000097:blood / Q000378:metabolism*; D006499:Hepatic Artery; D006503:Hepatic Veins; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D004317:Doxorubicin