Modulation of gemcitabine (2',2'-difluoro-2'-deoxycytidine) pharmacokinetics, metabolism, and Bioavailability in mice by 3,4,5,6-tetrahydrouridine
Modulation of gemcitabine (2',2'-difluoro-2'-deoxycytidine) pharmacokinetics, metabolism, and Bioavailability in mice by 3,4,5,6-tetrahydrouridine
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DOI：
10.1158/1078-0432.ccr-07-4885
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发表时间：
2008-06-01
影响因子：
11.5
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.
目的：在体内，2 '，2'-二氟-2 '-脱氧胞苷（dFdC）被肠道和肝脏胞苷脱氨酶（CD）快速灭活为2'，2 '-二氟-2'-脱氧尿苷（dFdU）。因此，dFdC具有差的口服生物利用度并且静脉内施用，伴随着相关的成本和给药时间表的限制。3，4，5，6-四氢尿苷（THU）是一种有效的CD抑制剂，口服生物利用度为20%。我们研究了THU的能力，以减少消除和首过效应的CD，从而使口服dFdC.Experimental Design：液相色谱-串联质谱法测定血浆dFdC和dFdU。小鼠用100 mg/kg dFdC i给药。v.或口服，有或没有100 mg/kg THU i. v.或口服。在5至1，440 min之间的特定时间，对小鼠（n = 3）实施安乐死。dFdC，dFdU，和THU浓度定量血浆和urine.Results：THU静脉注射和口服产生的浓度> 4 μ g/mL的3和2小时，分别，而浓度> 1 μ g/mL已与CD在体外几乎完全抑制。THU i. v.降低血浆dFdU浓度，但对dFdC i. v.给药后血浆浓度-时间曲线下dFdC血浆面积无影响。THU静脉注射和口服均显著增加了dFdC的口服生物利用度。口服dFdC的吸收率为59%，但只有10%通过肝脏和肠道CD并最终到达体循环。结论：与THU联合给药可使dFdC的口服生物利用度从10%提高到40%。口服dFdC治疗将更容易和更便宜，可能延长dFdC暴露，并能够探索静脉途径认为不切实际的给药方案。
Purpose: In vivo, 2',2'-difluoro-2'-deoxycytidine (dFdC) is rapidly inactivated by gut and liver cytidine deaminase (CD) to 2',2'-difluoro-2'-deoxyuridine (dFdU). Consequently, dFdC has poor oral bioavailability and is administered i.v., with associated costs and limitations in administration schedules. 3,4,5,6 -Tetrahydrouridine (THU) is a potent CD inhibitor with a 20% oral bioavailability. We investigated the ability of THU to decrease elimination and first-pass effect by CD, thereby enabling oral dosing of dFdC.Experimental Design: A liquid chromatography-tandem mass spectrometry assay was developed for plasma dFdC and dFdU. Mice were\ dosed with 100 mg/kg dFdC i. v. or orally with or without 100 mg/kg THU i.v. or orally. At specified times between 5 and 1,440 min, mice (n = 3) were euthanized. dFdC, dFdU, and THU concentrations were quantitated in plasma and urine.Results: THU i.v. and orally produced concentrations > 4 mu g/mL for 3 and 2 h, respectively, whereas concentrations of > 1 mu g/mL have been associated with near-complete inhibition of CD in vitro. THU i.v. decreased plasma dFdU concentrations but had no effect on dFdC plasma area under the plasma concentration versus time curve after i.v. dFdC dosing. Both THU i.v. and orally substantially increased oral bioavailability of dFdC. Absorption of dFdC orally was 59%, but only 10% passed liver and gut CD and eventually reached the systemic circulation. Coadministration of THU orally increased dFdC oral bioavailability from 10% to 40%.Conclusions: Coadministration of THU enables oral dosing of dFdC and warrants clinical testing. Oral dFdC treatment would be easier and cheaper, potentially prolong d FdC exposure, and enable exploration of administration schedules considered impractical by the i.v. route.