Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice.
Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice.
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DOI：
10.1007/s00280-010-1337-6
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发表时间：
2011-02
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.;Gilbert, Judith A.;Holleran, Julianne L.;Yellow-Duke, Archibong E.;Clausen, Dana M.;D'Argenio, David Z.;Ames, Matthew M.;Hershberger, Pamela A.;Parise, Robert A.;Bai, Lihua;Covey, Joseph M.;Egorin, Merrill J.
胞苷类药物，如吉西他滨，经过胞苷脱氨酶（CD）的快速分解代谢和失活。3,4,5,6-四氢吡啶（THU）是一种有效的CD抑制剂，已被应用于临床前和临床作为胞苷类似物代谢的调节剂。然而，THU只有20%的口服生物利用度，这限制了其临床前评估和临床应用。因此，我们对亲脂性更强的前药三乙酰-四氢THU （taTHU）给予小鼠后的四氢THU药代动力学进行了表征。小鼠分别静脉或口服150 mg/kg的taTHU。采用有效的LC-MS /MS法测定血浆和尿液THU浓度。计算血浆和尿液药代动力学参数。taTHU对CD没有抑制作用。150 mg/kg taTHU静脉注射后，THU的终末半衰期为235 min，血浆THU浓度为bb0.1 μ g/mL，该浓度显示对CD有抑制作用，持续10 h。肾脏排泄占taTHU静脉注射剂量的40-55%，占p.o. taTHU剂量的6-12%。产生THU的双室模型最适合静脉注射taTHU数据。taTHU在150 mg/kg p.o下产生浓度随时间变化的曲线，在0.5-2 h内平台值约为10µg/mL，随后下降，半衰期为122 min。静脉滴注THU约68%转化为THU，静脉滴注THU约30%转化为THU进入体循环，静脉滴注THU的利用率为30%，而静脉滴注THU的利用率为20%，这些数据将为临床研究提供支持。
Cytidine drugs, such as gemcitabine, undergo rapid catabolism and inactivation by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU is only 20% orally bioavailable, which limits its preclinical evaluation and clinical use. Therefore, we characterized THU pharmacokinetics after the administration to mice of the more lipophilic pro-drug triacetyl-THU (taTHU). Mice were dosed with 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC–MS/MS assay. Plasma and urine pharmacokinetic parameters were calculated non-compartmentally and compartmentally. taTHU did not inhibit CD. THU, after 150 mg/kg taTHU i.v., had a 235-min terminal half-life and produced plasma THU concentrations >1 µg/mL, the concentration shown to inhibit CD, for 10 h. Renal excretion accounted for 40–55% of the i.v. taTHU dose, 6–12% of the p.o. taTHU dose. A two-compartment model of taTHU generating THU fitted the i.v. taTHU data best. taTHU, at 150 mg/kg p.o., produced a concentration versus time profile with a plateau of approximately 10 µg/mL from 0.5–2 h, followed by a decline with a 122-min half-life. Approximately 68% of i.v. taTHU is converted to THU. Approximately 30% of p.o. taTHU reaches the systemic circulation as THU. The availability of THU after p.o. taTHU is 30%, when compared to the 20% achieved with p.o. THU. These data will support the clinical studies of taTHU.
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影响因子：
5.8
作者：
Hale, JT;Bigelow, JC;McCormack, JJ
通讯作者：
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影响因子：
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作者：
Beumer, Jan H.;Eiseman, Julie L.;Egorin, Merrill J.
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Egorin, Merrill J.
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Fenaux, Pierre
通讯作者：
Fenaux, Pierre
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作者：
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