title: Identification of an alginate-based formulation of paraquat to reduce the exposure of the herbicide following oral ingestion.
abstract: The herbicide paraquat has been widely used throughout the world for almost 50 years and is important in sustainable agriculture. When used correctly the chemical poses no known risk to human health. However, it is acutely toxic, and can be fatal, if the concentrated product is ingested orally. Despite many years of research there is no successful treatment for paraquat intoxication. In recent years we have turned our attention to understanding how we can make the product safer, if it is accidentally or intentionally consumed. We present in this paper a novel approach aimed at safening the paraquat product, Gramoxone. Following our previous research on the site and mechanism of paraquat absorption from the gastrointestinal tract we have identified a new formulation of paraquat, Gramoxone INTEON that reduces the absorption of paraquat into the blood. This new formulation contains the polysaccharide, alginate, a natural product extracted from sea-weed. We have designed a preparation of paraquat and alginate with surfactants that is herbicidally active but has the unique property that it gels on contact with gastric acid in the stomach. The resulting mixture slows the dispersion and delivery of the toxic chemical to its site of absorption in the small intestine. Alginates also protect the mucosa against the damaging influence of topical gastric irritants, like paraquat. Our studies have shown that increasing the loading of alginate between 7 and 17 g/L causes a dose-related reduction in paraquat absorption in vitro in isolated rat ileum. This is also observed in vivo, as measured by paraquat plasma kinetics in the rabbit where the Area Under Curve (AUC 0-24h) was reduced from 33.8+/-3 for Gramoxone to 12.5+/-6 (microg/mL)h for a formulation containing 17 g/L alginate. Such a reduction in systemic exposure to paraquat is expected to reduce the acute oral toxicity of the formulation. This should be particularly effective in a vomiting species such as man since we have shown in this investigation that alginates not only reduce the peak plasma paraquat values but also delay the time to peak levels. This provides the opportunity for a more effective emetic response since the highly viscous gelled material should remain in the stomach for longer than the liquid Gramoxone. Further research is required to understand and optimise the safening and herbicidal characteristics of these alginate acid-triggered gel formulations of paraquat. However, we anticipate that this alginate technology in Gramoxone INTEON could have significant benefit in reducing human mortalities associated with the herbicide.
authors.affiliation: Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, United Kingdom. jon.heylings@syngenta.com
authors.forename: J R
authors.initials: JR
authors.lastname: Heylings
authors.forename: M J
authors.initials: MJ
authors.lastname: Farnworth
authors.forename: C M
authors.initials: CM
authors.lastname: Swain
authors.forename: M J
authors.initials: MJ
authors.lastname: Clapp
authors.forename: B M
authors.initials: BM
authors.lastname: Elliott
mesh_terms: D000464:Alginates / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000863:Antacids / Q000494:pharmacology; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D006540:Herbicides / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007553:Isotope Labeling; D008297:Male; D010269:Paraquat / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity*; D011817:Rabbits; D051381:Rats