Dihydropyrimidine dehydrogenase activity and fluorouracil pharmacokinetics with liver damage induced by bile duct ligation in rats.
Hepatic metabolism is the main determinant in the pharmacokinetics of 5-fluorouracil (5-FU). Its disposition might be affected with liver dysfunction. In the present study, the influence of liver damage induced by bile duct ligation on dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in 5-FU catabolism, CYP2B, and 5-FU pharmacokinetics were compared in male Sprague-Dawley rats. After 3 weeks of the ligation in two different groups of animals for in vitro and pharmacokinetic experiments, significant increases in serum bilirubin level and spleen weight were found in both groups. No significant differences were noted in bilirubin level or spleen weight of the bile duct ligation group between the two experiment groups. In the in vitro experiment, DPD activity and protein levels determined by Western blot analysis in the bile duct ligation group were slightly but significantly greater than those of a sham-operated group, whereas CYP2B activity and protein level were significantly reduced. These findings were supported by mRNA levels of CYP2B and DPD. When 40 mg/kg 5-FU was administered i.v. in the pharmacokinetic experiment, no significant differences in pharmacokinetic parameters were found between the bile duct ligation and sham-operated groups. These results suggested that DPD activity and protein level were maintained and that 5-FU pharmacokinetics was not altered in the presence of liver damage accompanied by a significant reduction in CYP2B activity and protein level, supporting previous clinical studies showing that mild to moderate liver dysfunction does not affect 5-FU disposition.
Tateishi
T
T
Department of Pharmacology, St. Marianna University School of Medicine, Kanagawa, Japan.
Watanabe
M
M
Nakura
H
H
Tanaka
M
M
Kumai
T
T
Sakata
S F
SF
Tamaki
N
N
Ogura
K
K
Nishiyama
T
T
Watabe
T
T
Kobayashi
S
S
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D001652:Bile Ducts; D015152:Blotting, Northern; D001835:Body Weight; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000493:pharmacokinetics*; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009929:Organ Size; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil