Radiation Increases Bioavailability of Lisinopril, a Mitigator of Radiation-Induced Toxicities.
Radiation Increases Bioavailability of Lisinopril, a Mitigator of Radiation-Induced Toxicities.
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辐射增加了Lisinopril的生物利用度，Lisinopril是辐射引起的毒性的缓解剂。
DOI：
10.3389/fphar.2021.646076
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发表时间：
2021
影响因子：
5.6
通讯作者：
Szabo A
中科院分区：
文献类型：
--
作者：
Medhora M;Phadnis P;Narayanan J;Gasperetti T;Zielonka J;Moulder JE;Fish BL;Szabo A
没有FDA批准的药物可以减轻辐射攻击或核事故后可能发生的辐射暴露的延迟效应。迄今为止，血管紧张素转换酶抑制剂是缓解啮齿动物模型中造血、肺、肾和脑损伤的最成功的候选药物之一，并且可能减轻放疗后的延迟性辐射损伤。为了研究辐射的后期效应，开发了保留一条后腿部分的大鼠部分身体照射模型（腿外PBI），以同时将多个器官暴露于高剂量电离辐射并避免致命的血液学毒性。9到14戈伊的辐射会损害肠道和骨髓（急性辐射综合症），随后会对肺、心脏和肾脏造成延迟性损伤。本研究的目的是比较一种主要的血管紧张素转换酶（ACE）抑制剂赖诺普利在辐照与非辐照大鼠中的药代动力学（PK），作为FDA许可的一步。 方法：雌性WAG/RijCmcr大鼠，给予12.5 ~ 13戈伊的外腿照射。在照射后第35天，在损伤的潜伏期内，照射和未照射的同胞接受了单次灌胃（0.3 mg，0.6 mg）或静脉注射（0.06 mg）赖诺普利。在不同时间点测定血浆、尿液、肺、肝和肾中赖诺普利的浓度。进行PK建模（R软件包）以追踪赖诺普利在不同隔室中的分布。 结果如下：双室（中心血浆和外周）PK模型最适合赖诺普利测量，具有两个额外的组分，灌胃和尿液。未辐照和辐照动物之间的吸收率和肾脏清除率相似（分别为：比值0.883，p = 0.527; 0.943，p = 0.605）。辐照大鼠的房室间清除率（从血浆到外周）低于未辐照大鼠（比值0.615，p = 0.003），而药物的生物利用度高33%（比值= 1.326，p < 0.001）。 释义：由于赖诺普利的受体存在于血管内皮细胞中，而辐射会诱导血管退化，因此受辐射大鼠体内赖诺普利的结合量可能会减少，从而增加药物的循环水平。然而，本研究不能排除大鼠照射后赖诺普利的长期吸收或排泄总量的变化。
There are no FDA-approved drugs to mitigate the delayed effects of radiation exposure that may occur after a radiological attack or nuclear accident. To date, angiotensin-converting enzyme inhibitors are one of the most successful candidates for mitigation of hematopoietic, lung, kidney, and brain injuries in rodent models and may mitigate delayed radiation injuries after radiotherapy. Rat models of partial body irradiation sparing part of one hind leg (leg-out PBI) have been developed to simultaneously expose multiple organs to high doses of ionizing radiation and avoid lethal hematological toxicity to study the late effects of radiation. Exposures between 9 and 14 Gy damage the gut and bone marrow (acute radiation syndrome), followed by delayed injuries to the lung, heart, and kidney. The goal of the current study is to compare the pharmacokinetics (PK) of a lead angiotensin converting enzyme (ACE) inhibitor, lisinopril, in irradiated vs. nonirradiated rats, as a step toward licensure by the FDA. Methods: Female WAG/RijCmcr rats were irradiated with 12.5–13 Gy leg-out PBI. At day 35 after irradiation, during a latent period for injury, irradiated and nonirradiated siblings received a single gavage (0.3 mg, 0.6 mg) or intravenous injection (0.06 mg) of lisinopril. Plasma, urine, lung, liver and kidney levels of lisinopril were measured at different times. PK modeling (R package) was performed to track distribution of lisinopril in different compartments. Results: A two-compartment (central plasma and periphery) PK model best fit lisinopril measurements, with two additional components, the gavage and urine. The absorption and renal clearance rates were similar between nonirradiated and irradiated animals (respectively: ratios 0.883, p = 0.527; 0.943, p = 0.605). Inter-compartmental clearance (from plasma to periphery) for the irradiated rats was lower than for the nonirradiated rats (ratio 0.615, p = 0.003), while the bioavailability of the drug was 33% higher (ratio = 1.326, p < 0.001). Interpretation: Since receptors for lisinopril are present in endothelial cells lining blood vessels, and radiation induces vascular regression, it is possible that less lisinopril remains bound in irradiated rats, increasing circulating levels of the drug. However, this study cannot rule out changes in total amount of lisinopril absorbed or excreted long-term, after irradiation in rats.
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影响因子：
2.2
作者：
Booth C;Tudor G;Tudor J;Katz BP;MacVittie TJ
通讯作者：
MacVittie TJ
影响因子：
3.4
作者：
Moulder JE;Cohen EP;Fish BL
通讯作者：
Fish BL
影响因子：
3.4
作者：
Gao F;Fish BL;Moulder JE;Jacobs ER;Medhora M
通讯作者：
Medhora M
影响因子：
2.6
作者：
Baker JE;Fish BL;Su J;Haworth ST;Strande JL;Komorowski RA;Migrino RQ;Doppalapudi A;Harmann L;Allen Li X;Hopewell JW;Moulder JE
通讯作者：
Moulder JE
影响因子：
2.2
作者：
Fish, Brian L.;Gao, Feng;Medhora, Meetha
通讯作者：
Medhora, Meetha