Towards "CO in a pill": Pharmacokinetic studies of carbon monoxide prodrugs in mice.
Towards "CO in a pill": Pharmacokinetic studies of carbon monoxide prodrugs in mice.
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DOI：
10.1016/j.jconrel.2020.07.040
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发表时间：
2020-11-10
期刊：
影响因子：
--
通讯作者：
Tan C
中科院分区：
文献类型：
--
作者：
Wang M;Yang X;Pan Z;Wang Y;De La Cruz LK;Wang B;Tan C
一氧化碳（CO）是一种已知的内源性信号分子，在治疗炎症、癌症、神经保护和镰状细胞病等方面具有潜在的治疗适应症。使用CO作为治疗剂的障碍之一是开发用于各种适应症的药学上可接受的递送形式。沿着这条路线，我们已经开发了有机CO前药，其允许将这种气体分子包装成剂型，以实现“药丸中的一氧化碳”的目标。这应该能够实现非吸入给药，包括口服和静脉内途径。这些前药先前已在多种动物模型中证明了功效。为了进一步了解这些前药的CO递送效率与其功效的关系，我们对这些前药进行了第一次药代动力学研究。在此过程中，我们选择了五种具有不同CO释放动力学的代表性前药，并通过口服、腹膜内和静脉途径给药后检查了其药代动力学。结果发现，所有三种途径都能够提高全身CO水平，递送效率依次为静脉，口服和腹腔途径。CO前药及其CO释放产物易于从循环中清除。CO前药在口服CO递送和体内最小药物蓄积方面显示出有前途的药学性质。这是首次研究CO释放动力学、CO前药清除率、给药途径和CO递送效率之间的相互作用。
Carbon monoxide (CO) is a known endogenous signaling molecule with potential therapeutic indications in treating inflammation, cancer, neuroprotection, and sickle cell disease among many others. One of the hurdles in using CO as a therapeutic agent is the development of pharmaceutically acceptable delivery forms for various indications. Along this line, we have developed organic CO prodrugs that allow for packing this gaseous molecule into a dosage form for the goal of “carbon monoxide in a pill.” This should enable non-inhalation administration including oral and intravenous routes. These prodrugs have previously demonstrated efficacy in multiple animal models. To further understand the CO delivery efficiency of these prodrugs in relation to their efficacy, we undertook the first pharmacokinetic studies on these prodrugs. In doing so, we selected five representative prodrugs with different CO release kinetics and examined their pharmacokinetics after administration via oral, intraperitoneal, and intravenous routes. It was found that all three routes were able to elevate systemic CO level with delivery efficiency in the order of intravenous, oral, and intraperitoneal routes. CO prodrugs and their CO-released products were readily cleared from the circulation. CO prodrugs demonstrate promising pharmaceutical properties in terms of oral CO delivery and minimal drug accumulation in the body. This represents the very first study of the interplay among CO release kinetics, CO prodrug clearance, route of administration, and CO delivery efficiency.
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