Locoregional application of 5-fluorouracil to the liver: alteration of pharmacokinetics and bone marrow toxicity in rats with thioacetamide-induced cirrhosis.
Pharmacokinetics and toxicity of 5-fluorouracil (5-FU) applied intra-arterially into the liver were studied in control and cirrhotic rats. Cirrhosis was induced by administering thioacetamide (4.5 mg/rat X day) over 6 months. 5-FU was administered into the hepatic artery at 30 mg/kg b.w. by bolus injection followed by infusion of 0.63 mg/kg X min for 40 min. Pharmacokinetics of 5-FU in plasma was studied by HPLC analysis. 5-FU induced toxicity was examined in a second group of control and cirrhotic rats at 48 and 168 hours after treatment with 5-FU (31.4 mg/kg b.w.) infused into the liver artery for 1 h. Analysis of toxicity was carried out by determining liver enzymes in plasma, bone marrow cellularity and colony forming units in vitro (CFU-C) and in vivo (CFU-S). The results indicate that during the period investigated (85 min) 5-FU was not eliminated from the plasma of cirrhotic rats in contrast to controls. The constant level of 5-FU in the plasma of cirrhotic rats induced a considerably higher myelosuppression in these animals, than the short-lived 5-FU peak in controls.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000378:metabolism* / Q000633:toxicity; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013853:Thioacetamide / Q000633:toxicity
D013853:Thioacetamide; D000410:Alanine Transaminase; D005472:Fluorouracil