Relationships among plasma [2-(13)C]uracil concentrations, breath (13)CO(2) expiration, and dihydropyrimidine dehydrogenase (DPD) activity in the liver in normal and dpd-deficient dogs.
Dihydropyrimidine dehydrogenase (DPD), the first enzyme in the sequential metabolism of pyrimidine, regulates blood concentrations of 5-fluorouracil and is deeply involved in its toxicity. This study was designed to examine the effects of a DPD inhibitor on blood concentrations of [2-(13)C]uracil ([(13)C]uracil) and (13)CO(2) concentration (Delta(13)C) expired in breath after oral or intravenous administration of [(13)C]uracil to DPD-suppressed dogs prepared by pretreatment with 5-(trans-2-bromovinyl)uracil (BVU), a DPD inhibitor. Area under the curve (AUC(t)) of [(13) C]uracil after oral administration at 20 micromol/kg to dogs pretreated with BVU at 2, 5, and 40 mmol/kg were 37-, 88- and 120-fold higher than those of the control dogs, respectively. In contrast, breath AUC(t) values of Delta(13)C were reduced to 0.88-, 0.47- and 0.13-fold the control values, respectively. Upon intravenous administration of [(13)C]uracil at 20 micromol/kg to dogs pretreated with BVU at 0.5, 2, and 40 micromol/kg, blood AUC(t) values of [(13)C]uracil were 1.4-, 4.2-, and 13-fold higher than those of the control group, respectively, whereas breath AUC(t) values were reduced to 1.0-, 0.83-, and 0.07-fold the respective control values. DPD activities in the liver cytosol of dogs pretreated with BVU at 0.5, 2, 5, and 40 micromol/kg were decreased to 0.71-, 0.12-, 0.06-, and 0.04-fold those of the control dogs, respectively. These findings demonstrate that breath output (Delta(13)C) is a good marker of hepatic DPD activity in vivo.
Inada
Makoto
M
Otsuka Pharmaceutical Co., Ltd., 224-18 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0182, Japan. inadam@otsuka.jp
Hirao
Yukihiro
Y
Koga
Toshihisa
T
Itose
Minoru
M
Kunizaki
Jun-Ichi
J
Shimizu
Takefumi
T
Sato
Hitoshi
H
D000284:Administration, Oral; D000818:Animals; D001944:Breath Tests; D001976:Bromouracil / Q000031:analogs & derivatives / Q000494:pharmacology; D002245:Carbon Dioxide / Q000032:analysis* / Q000378:metabolism; D002247:Carbon Isotopes; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004285:Dogs; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology*; D008297:Male; D014498:Uracil / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics
D002247:Carbon Isotopes; D002245:Carbon Dioxide; D001976:Bromouracil; D014498:Uracil; C046140:5-(2-bromovinyl)uracil; D042943:Dihydrouracil Dehydrogenase (NADP)