Towards "CO in a pill": Pharmacokinetic studies of carbon monoxide prodrugs in mice

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.