Received for publication July 20, 2004.
Revised December 16, 2004.
Accepted for publication December 17, 2004.

Relationships among plasma [2-¹³C]uracil concentrations, breath ¹³CO₂-expiration, and DPD activity in the liver in normal and DPD-deficient dogs

Abstract

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 [2-¹³C]uracil (¹³C-uracil) and ¹³CO₂ concentration (¹³C) expired in breath after oral or intravenous administration of ¹³C-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 ¹³C-uracil after oral administration at 20 µmol/kg to dogs pretreated with BVU at 2, 5, and 40 µmol/kg were 37-, 88- and 120-fold higher than those of the control dogs, respectively. In contrast, breath AUC_t of ¹³C were reduced to 0.88-, 0.47- and 0.13-fold the control values, respectively. On intravenous administration of ¹³C-uracil at 20 µmol/kg to dogs pretreated with BVU at 0.5, 2, and 40 µmol/kg, blood AUC_tvalues of ¹³C-uracil were 1.4-, 4.2- and 13-fold higher than those of the control group, respectively, while breath AUC_t 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 µmol/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 (¹³C) is a good marker of hepatic DPD activity in vivo.

Key words: drug clearance, drug interactions, enzyme inhibitors, kinetics

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