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When introducing new active substances into ophthalmic treatments, it is crucial to assess the risk of side effects caused by the systemic action of the active compound. The succinic salt of polyhexamethylene guanidine derivative (ss-PHMGd) has shown high in vitro activity. This study aimed to evaluate the systemic effects of ss-PHMGd-based eye drops after ocular instillation in a preclinical model. Simple mathematical models were used to calculate pharmacokinetic parameters during instillation in two types of laboratory animals: guinea pigs and chinchilla rabbits. Groups received intravenous injections and ocular treatments. Tritium-labeled ss-PHMGd was used to quantify its concentration in organs and tissues. To test the linearity of the parameter relationships, data from three different doses were compared. Renal excretion was studied by quantifying ss-PHMGd concentrations in urine using radiometric methods. The results showed that ss-PHMGd-based eye drops present a low risk of systemic side effects and exhibit minimal penetration into other organs after instillation. No species-specific differences were found in the ADME parameters of the preclinical models (the guinea pig-to-chinchilla rabbit absorption ratio was 0.7). The AUC-D parameters exhibited a linear relationship for doses ranging from 0.5 of therapeutic dose (TD) to 5TD in guinea pigs. Renal excretion analysis revealed that 5.3% of the administered dose was excreted through the kidneys, indicating significant metabolic transformation or excretion via other pathways. This study enhances the understanding of the pharmacokinetics and safety of polyguanidines, with implications for toxicology and risk assessment.<\/jats:p>","DOI":"10.5620\/eaht.2025027","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T06:10:47Z","timestamp":1764915047000},"page":"e2025027","update-policy":"https:\/\/doi.org\/10.5620\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical pharmacokinetics and tissue distribution of a polyhexamethylene guanidine derivative after ocular mucosal 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