5-ETHYNYL-2(1H)-PYRIMIDINONE - ALDEHYDE OXIDASE-ACTIVATION TO 5-ETHYNYLURACIL, A MECHANISM-BASED INACTIVATOR OF DIHYDROPYRIMIDINE DEHYDROGENASE

5-Ethynyluracil is a potent mechanism-based inactivator of dihydropyri midine dehydrogenase (DPD, EC 1.3.1.2) in vitro (Porter et al., J Biol Chem 267: 5236-5242, 1992) and in vivo (Spector et al., Biochem Pharm acol, 46: 2243-2248, 1993. 5-Ethynyl-2(1H)-pyrimidinone was rapidly ox idized to 5-ethynyluracil by aldehyde oxidase. The substrate efficienc y (k(cat)/K-m) was 60-fold greater than that for N-methylnicotinamide. In contrast, xanthine oxidase oxidized 5-ethynyl-2(1H)-pyrimidinone t o 5-ethynyluracil with a substrate efficiency that was only 0.02% that of xanthine. Because 5-ethynyl-2(1H)-pyrimidinone did not itself inac tivate purified DPD in vitro and aldehyde oxidase is predominately fou nd in liver, we hypothesized that 5-ethynyl-2(1H)-pyrimidinone could b e a liver-specific inactivator of DPD. We found that 5-ethynyl-2(1H)-p yrimidinone administered orally to rats at 2 mu g/kg inactivated DPD i n all tissues studied. Although 5-ethynyl-2(1H)-pyrimidinone produced slightly less inactivation than 5-ethynyluracil, the two compounds sho wed fairly similar patterns of inactivation of DPD in these tissues. A t doses of 20 mu g/kg, however, 5-ethynyl-2-pyrimidinone and 5-ethynyl uracil produced equivalent inactivation of DPD. Thus, 5-ethynyl-2(1H)- pyrimidinone appeared to be an efficient, but not highly liver-selecti ve prodrug of 5-ethynyluracil.