Pharmacokinetics, metabolism, and oral bioavailability of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine in mice
Pharmacokinetics, metabolism, and oral bioavailability of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine in mice
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DOI：
10.1158/1078-0432.ccr-06-1250
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发表时间：
2006-12-15
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，5-氟-2 '-脱氧胞苷（FdCyd）快速并依次转化为5-氟-2'-脱氧尿苷、5-氟尿嘧啶和5-氟尿嘧啶。FdCyd和3，4，5，6-四氢尿苷（THU）（一种阻断FdCyd催化剂中第一代谢步骤的胞苷脱氨酶（CD）抑制剂）的静脉内组合正在临床上研究其抑制DNA甲基转移酶的能力。然而，THU对FdCyd代谢和药代动力学的全部影响尚不清楚。我们的目的是表征FdCyd的药代动力学，代谢和生物利用度与和没有THU在mice.Experimental Design. We开发了一种灵敏的高效液相色谱串联质谱测定定量FdCyd和代谢产物在小鼠血浆中。小鼠静脉内或口服给药。与25 mg/kg FdCyd联合施用或不联合施用100 mg/kg THU p.o.结果：FdCyd单药的口服生物利用度约为4%。与THU联合给药增加了FdCyd的暴露量，降低了其代谢产物的暴露量; i. v.和p.o.联合施用THU增加了对p.o. FdCyd分别增加87倍和58倍。口服后的FdCyd暴露FdCyd（含p.o.）THU是多达54%，静脉注射FdCyd与静脉注射THU.Conclusions：FdCyd吸收良好，但经历大量的首过催化剂的CD潜在的毒性代谢产物，不抑制DNA甲基转移酶。THU具有足够的生物利用度，可降低CD对FdCyd的首过效应。THU和FdCyd的口服联合给药是一种很有前途的方法，值得临床测试，因为它可以长期维持有效的FdCyd浓度，这比目前已批准或正在开发的其他DNA甲基转移酶抑制剂具有优势。
Purpose: In vivo, 5-fluoro-2'-deoxycytidine (FdCyd) is rapidly and sequentially converted to 5-fluoro-2'-deoxyuridine, 5-fluorouracil, and 5-fluorouridine. The i.v. combination of FdCyd and 3,4,5,6-tetrahydrouridine (THU), a cytidine deaminase (CD) inhibitor that blocks the first metabolic step in FdCyd catabolism, is being investigated clinically for its ability to inhibit DNA methyltransferase. However, the full effects of THU on FdCyd metabolism and pharmacokinetics are unknown. We aimed to characterize the pharmacokinetics, metabolism, and bioavailability of FdCyd with and without THU in mice.Experimental Design: We developed a sensitive high-performance liquid chromatography tandem mass spectrometry assay to quantitate FdCyd and metabolites in mouse plasma. Mice were dosed i.v. or p.o. with 25 mg/kg FdCyd with or without coadministration of 100 mg/kg THU p.o. or i.v.Results: The oral bioavailability of FdCyd alone was similar to 4%. Coadministration with THU increased exposure to FdCyd and decreased exposure to its metabolites; i.v. and p.o. coadministration of THU increased exposure to p.o. FdCyd by 87- and 58-fold, respectively. FdCyd exposure after p.o. FdCyd with p.o. THU was as much as 54% that of i.v. FdCyd with i.v. THU.Conclusions: FdCyd is well absorbed but undergoes substantial first-pass catabolism by CD to potentially toxic metabolites that do not inhibit DNA methyltransferase. THU is sufficiently bioavailable to reduce the first-pass effect of CD on FdCyd. Oral coadministration of THU and FdCyd is a promising approach that warrants clinical testing because it may allow maintaining effective FdCyd concentrations on a chronic basis, which would be an advantage over other DNA methyltransferase inhibitors that are currently approved or in development.