Addressing critical gaps in understanding the in vivo behavior of polyethylene glycol (PEG)-based excipients, this study systematically elucidates the biological fate of methoxy-PEG₆-hydroxyl (M-PEG₆-OH) through comprehensive pharmacokinetic and metabolic investigations in rats. Employing a validated ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) methodology, we reveal distinctive biodistribution characteristics including rapid systemic clearance (Half-life (t 1/2 ) = 1.92 ± 1.16 h) and extensive tissue penetration (Apparent volume of distribution (V d ) = 0.84 ± 0.45 L/kg), suggesting efficient extravascular dissemination. Excretion pathways analysis demonstrated predominant renal elimination, with 59.03 % of the administered dose recovered in urine within 48 h post-IV injection, contrasting with minimal fecal excretion (0.99 %). Quantitative metabolite profiling identified M-PEG₅-CH₂COOH as the oxidative transformation product through terminal hydroxyl modification. The significantly higher relative abundance of metabolites (M-PEG 5 -CH 2 COOH) in urine compared to feces within the same time period provides critical insights into the biotransformation processes and metabolic pathways of the PEG polymer. These findings establish the first systematic evidence of metabolic trajectory and elimination mechanisms for M-PEG-OH, offering vital references for optimizing PEGylated drug delivery systems with enhanced biocompatibility and predictable safety profiles.
ABSTRACT Pharmacokinetic changes induced by radiation following radiotherapy (“RT-PK” phenomenon) are of great significance to the effectiveness and safety of chemotherapeutic agents in clinical settings. The aims of this study were to clarify the organic anion transporters (Oats) involved in the “RT-PK” phenomenon of bestatin in rats following X-ray irradiation and to elucidate its potential mechanism via vitamin D signalling. Pharmacokinetic studies, uptake assays using rat kidney slices and primary proximal tubule cells, and molecular biological studies were performed. Significantly increased plasma concentrations and systemic exposure to bestatin were observed at 24 and 48 h following abdominal X-ray irradiation, regardless of oral or intravenous administration of the drugs in rats. Reduced renal clearance and cumulative urinary excretion of bestatin were observed at 24 and 48 h post-irradiation in rats following intravenous administration. The uptake of the probe substrates p -aminohippuric acid and oestrone 3-sulphate sodium in vitro and the expression of Oat1 and Oat3 in vivo were reduced in the corresponding models following irradiation. Moreover, the upregulation of the vitamin D receptor (Vdr) in mRNA and protein levels negatively correlated with the expressions and functions of Oat1 and Oat3 following irradiation. Additionally, elevated plasma urea nitrogen levels and histopathological changes were observed in rats after exposure to irradiation. The “RT-PK” phenomenon of bestatin occurs in rats after exposure to irradiation, possibly resulting in the regulation of the expressions and activities of renal Oats via activation of the Vdr signalling pathway.
High energy ionizing radiation was widely used in medical diagnosis and cancer radiation therapy. The high dose of X ray or γ ray can cause the damage of cancerous tissue as well as healthy tissue during therapy. Therefore, it is urgent to develop chemical agents to protect
the healthy tissue from high energy ray invasion. Here, the ultrasmall Pt clusters were employed as the anti-radiation agents for protecting healthy cells and improving survival rate of irradiated mice. It was found that Pt clusters can reduce the DNA damages in irradiated cells. In vivo
experiments show that the Pt clusters treatment can improve the survival rate of irradiated mice up to 30%. As a contrast, only-irradiated mice without Pt clusters treatment completely died after 15 days. The detailed biological experiments showed that Pt clusters can recover the bone marrow
DNA level and superoxide dismutase activities via scavenging free radicals. Importantly, the ultrasmall Pt clusters can be excreted rapidly by kidney and do not cause long-term toxicity.
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