Riccardi R, Chabner B, Glaubiger D L, Wood J, Poplack D G
Cancer Res. 1982 May;42(5):1736-9.
Tetrahydrouridine (THU), a potent inhibitor of cytidine deaminase, has been shown to increase the antitumor activity of 1-beta-D-arabinofuranosylcytosine (ara-C) both in vitro and in vivo. In initial studies, which examined the cerebrospinal fluid (CSF) pharmacokinetics of intrathecally (i.t.) administered THU, the drug was found to be slowly cleared from the CSF with alpha and beta half-lives of 1 and 8 hr, respectively. In subsequent experiments, both i.v. pretreatment with THU and concomitant i.t. injection of THU were found to retard the disappearance of i.t. ara-C from the CSF, although the effect of i.t. THU was more profound. ara-C given alone was cleared from CSF with alpha and beta half-lives of 27.5 +/- 6.7 and 115.6 +/- 0.4 (S.D.) min, respectively. Pretreatment with i.v. THU resulted in alpha and beta half-lives of 10.4 +/- 1.5 and 85.7 +/- 11.1, respectively, whereas concomitant administration of i.t. THU resulted in a single half-life of 96 +/- 0.7. The mean calculated clearance rates for ara-C alone, ara-C plus i.v. THU, and ara-C plus i.t. THU were 7.5, 6.2, and 4.2 ml/hr, respectively. This effect appeared to be primarily due to THU inhibition of ara-C deamination, since a decrease in formation of 1-beta-D-arabinofuranosyluracil in the CSF was observed when ara-C was given in the presence of THU (either i.t. or i.v.). No acute neurotoxicity was noted after administration of either i.t. THU alone or i.t. THU with ara-C. The ability of THU to alter CSF ara-C pharmacokinetics may have potential therapeutic value.
四氢尿苷（THU）是一种有效的胞苷脱氨酶抑制剂，已证实在体外和体内均可增强1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷，ara-C）的抗肿瘤活性。在最初研究鞘内注射THU的脑脊液（CSF）药代动力学时，发现该药物从CSF中清除缓慢，α和β半衰期分别为1小时和8小时。在随后的实验中，发现静脉注射THU预处理以及同时鞘内注射THU均可延缓鞘内注射的ara-C从CSF中消失，尽管鞘内注射THU的效果更显著。单独给予的ara-C从CSF中清除，α和β半衰期分别为27.5±6.7分钟和115.6±0.4（标准差）分钟。静脉注射THU预处理导致α和β半衰期分别为10.4±1.5分钟和85.7±11.1分钟，而同时鞘内注射THU导致单一半衰期为96±0.7分钟。单独的ara-C、ara-C加静脉注射THU以及ara-C加鞘内注射THU的平均计算清除率分别为7.5、6.2和4.2 ml/小时。这种作用似乎主要是由于THU对ara-C脱氨的抑制，因为当在THU（鞘内或静脉注射）存在的情况下给予ara-C时，观察到CSF中1-β-D-阿拉伯呋喃糖基尿嘧啶的形成减少。单独鞘内注射THU或鞘内注射THU与ara-C联用后均未观察到急性神经毒性。THU改变CSF中ara-C药代动力学的能力可能具有潜在的治疗价值。
