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RELATIONSHIPS AMONG PLASMA [2-¹³C]URACIL CONCENTRATIONS, BREATH ¹³CO₂ EXPIRATION, AND DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) ACTIVITY IN THE LIVER IN NORMAL AND DPD-DEFICIENT DOGS

Research Section, Diagnostics Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan (M.In., M.It., J.K., T.S.); Department of Drug Metabolism, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan (Y.H., T.K., M.In., M.It.); and Department of Clinical and Molecular Pharmacokinetics/Pharmacodynamics, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan (H.S.)

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 [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 ¹³C 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 (¹³C) is a good marker of hepatic DPD activity in vivo.

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