Plasma pharmacokinetics and oral bioavailability of 3,4,5,6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice
Plasma pharmacokinetics and oral bioavailability of 3,4,5,6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice
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DOI：
10.1007/s00280-007-0625-2
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发表时间：
2008-08-01
影响因子：
3
通讯作者：
Egorin, Merrill J.
中科院分区：
文献类型：
--
作者：
Beumer, Jan H.;Eiseman, Julie L.;Egorin, Merrill J.
胞苷类似物，如胞嘧啶阿拉伯糖苷、吉西他滨、地西他滨、5-氮杂胞苷、5-氟-2'-脱氧胞苷和5-氯-2'-脱氧胞苷会被胞苷脱氨酶 (CD) 快速分解代谢。 3,4,5,6-四氢尿苷 (THU) 是一种有效的 CD 抑制剂，已作为胞苷类似物代谢调节剂应用于临床前和临床。然而，THU 药代动力学尚未完全表征，这损害了 THU 的最佳临床前评估和临床使用。因此，我们表征了 THU 在小鼠中的药代动力学和生物利用度。小鼠静脉注射 THU（100 毫克/公斤）或口服（30、100 或 300 毫克/公斤）。通过经过验证的 LC-MS/MS 测定对血浆和尿液 THU 浓度进行定量。分室和非室计算血浆药代动力学参数。 THU，100 mg/kg iv 的终末半衰期为 73 分钟，产生的血浆 THU 浓度> 1 μg/ml，该浓度可有效阻断脱氨作用，持续 4 小时。清除率为9.1ml/min/kg，分配体积为0.95l/kg。肾脏排泄占THU剂量的36-55%。三室模型最适合 iv THU 数据。 THU，以 100 mg/kg 口服，产生浓度与时间的关系曲线，在 0.5-3 小时内达到约 10 μg/ml 的平台，随后下降，半衰期为 85 分钟。 THU的口服生物利用度约为20%。 THU 20% 的口服生物利用度足以产生并维持几个小时抑制 CD 的血浆浓度。这表明使用 THU 来减少 CD 对胞苷类似物的消除和首过代谢的可行性。 THU 药代动力学目前正在人体中进行评估。
Cytidine analogues such as cytosine arabinoside, gemcitabine, decitabine, 5-azacytidine, 5-fluoro-2'-deoxycytidine and 5-chloro-2'-deoxycytidine undergo rapid catabolism by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU) is a potent CD inhibitor that has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU pharmacokinetics has not been fully characterized, which has impaired the optimal preclinical evaluation and clinical use of THU. Therefore, we characterized the THU pharmacokinetics and bioavailability in mice. Mice were dosed with THU iv (100 mg/kg) or po (30, 100, or 300 mg/kg). Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma pharmacokinetic parameters were calculated compartmentally and non-compartmentally. THU, at 100 mg/kg iv had a 73 min terminal half-life and produced plasma THU concentrations > 1 mu g/ml, the concentration shown to effectively block deamination, for 4 h. Clearance was 9.1 ml/min/kg, and the distribution volume was 0.95 l/kg. Renal excretion accounted for 36-55% of the THU dose. A three-compartment model fit the iv THU data best. THU, at 100 mg/kg po, produced a concentration versus time profile with a plateau of approximately 10 mu g/ml from 0.5-3 h, followed by a decline with an 85 min half-life. The oral bioavailability of THU was approximately 20%. The 20% oral bioavailability of THU is sufficient to produce and sustain, for several hours, plasma concentrations that inhibit CD. This suggests the feasibility of using THU to decrease elimination and first-pass metabolism of cytidine analogues by CD. THU pharmacokinetics are now being evaluated in humans.