RELATIONSHIPS AMONG PLASMA [2-13C]URACIL CONCENTRATIONS, BREATH13CO2EXPIRATION, AND DIHYDROPYRIMIDINE DEHYDROGENASE (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 (Δ¹³C) 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 [¹³ C]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 values of Δ¹³C were reduced to 0.88-, 0.47- and 0.13-fold the control values, respectively. Upon intravenous administration of [¹³C]uracil at 20 μmol/kg to dogs pretreated with BVU at 0.5, 2, and 40 μmol/kg, blood AUC_t values of [¹³C]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 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 (Δ¹³C) is a good marker of hepatic DPD activity in vivo.