["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Schematic illustrating mechanisms underlying direct vascular absorption and subsequent movement of venom toxins into the tissues consequent to snakebite. A, snakebite into prey deposits venom toxins into the tissue interstitium, with the venom then causing acute inflammation primarily in venules. B, venom toxins directly absorb into the bloodstream by diffusing through inflammation‐activated pores (IAPs). Direct vascular absorption is inhibited with increases in venular pressure (PV) (e.g. for bites to human lower limbs when standing or due to a pressure cuff) because of counteracting plasma outflow (see text for lymphatic contribution). C, venoms once in the bloodstream cause widespread inflammation and distributed opening of IAPs, markedly enhancing distributed venom toxin movement from the blood into the tissues. Images in A are generated by ChatGPT‐4o (Open AI, 2025), and those in B and C are partly created using BioRender (version 3.0; April 2026). Figure compiled and partly annotated using Microsoft PowerPoint. Abbreviations: πv and πi, blood and interstitial colloid osmotic pressure, respectively; Pv, intravenular pressure; Pi, interstitial pressure.\n\n\n\n\n\n\n\n\n\nAbstract\nSnake envenomation activates the immune system through permeability‐increasing factors that generate an acute vascular inflammatory response by opening large inflammation‐activated pores (IAPs) in the microvasculature. These events facilitate the exudation of plasma from blood into body tissues. However we show that IAPs also allow macromolecules, including venom toxins, to flood directly into the bloodstream, even against an outflow of plasma solutes. Such inflammation‐facilitated macromolecular absorption (IFMA) acts together with lymphatic absorption and has a physiological role in removing interstitial molecules, as evidenced by our dextran studies. IFMA will function in vascular absorption of interstitial molecules, potentially up to the radius of IAPs, which we determined to be 21 nm (95% confidence interval (CI) 18–24 nm). This absorption depends on factors, including the interstitial–vascular concentration gradient, the reflection coefficient of each molecule and microvascular pressure. Molecules absorbed will include snake venom toxins and various cellular breakdown products that arise during processes such as the inflammatory phase of wound healing. Most, if not all, venom toxins will be absorbed, as these typically have a hydrodynamic radius (r0) of 1–6 nm, which is well below that of IAPs. Notably once in the circulation venoms cause distributed inflammation, enhancing venom toxin movement from the bloodstream into the tissues. These mechanisms markedly increase the absorption of often lethal snake toxins and ensure their dissemination throughout body tissues, facilitating prey capture and adding to make snakebite extremely dangerous to humans. These findings provide mechanistic insight into current empirical snakebite first aid and present directions that may improve these procedures.\n\n\n\n\n\n\n\n\n\nKey points\n\nSnake venoms induce acute vascular inflammation, manifested by the opening of large pores termed inflammation‐activated pores (IAPs), which we experimentally measure to have a radius of 21 nm.\nThese pores mediate well‐known exudation of plasma proteins but simultaneously provide a pathway for absorption of macromolecules, including venoms, a process that operates in parallel with the lymphatic system in clearing interstitial macromolecules.\nAlthough utilized in snakebite envenomation, such inflammation‐facilitated macromolecular absorption (IFMA) is likely to have important physiological or pathophysiological roles, candidates including clearance of cellular breakdown products during the inflammatory phase of wound healing.\nOnce in the vasculature venoms induce distributed inflammation of the IAPs, facilitating the exudation of venom toxins into tissues.\nThe findings together with a model based on our experimental data provide new directions for improving snakebite first aid and present experimental evidence for a mechanism that operates to clear interstitial macromolecules.\n\n\n"]