Bipyridyl Compounds

What are Bipyridyl Compounds?

Bipyridyl compounds, most notably paraquat and diquat, are commercial herbicides. Paraquat and diquat are bis-quarternary ammonium compounds that each contain a bipyridyl ring and are divalent cations associated with anions; chloride for paraquat and bromide for diquat.¹ Paraquat is the more toxic of these compounds, and has one of the highest acute toxicities of herbicides.² However, both compounds are inactivated by clay soils and ultraviolet light, so there is little risk of chronic exposure. Most toxic events involving bipyridyl compounds are due to accidental or intentional ingestion.¹

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Figure 1: Chemical structures of Paraquat and Diquat, two well known bipyridyl compound herbicides²

What are the Toxicokinetics of Bipyridyl Compounds?

Only a small amount of data is available on the pharmacokinetics/toxicokinetics of bipyridyl compounds. From one Sri Lankan population analysis on paraquat, there appears to be a clearance of 1.17 L/h, a volume of distribution of 2.4 L/kg, and a half-life of 87 hours.¹ Peak plasma concentration in humans is thought to be around 4 hours.¹ The toxicity of paraquat depends greatly on the species, route of exposure, and concentration of solution. Rats appear to have a higher tolerance to paraquat than other species, including humans.² There is also a difference in absorption between species; rats only absorb 1-5% of an oral dose where dogs (and presumably humans) absorb around 45-65% of an oral dose.¹

The intraperitoneal route is the most toxic, followed by the oral route. Absorption and inhalation rarely cause toxicity.² Bipyridyl compounds are excreted through urine, with a large amount of the dose eliminated in the first few hours after ingestion, unchanged. This elimination starts to slow as renal damage occurs and renal function deteriorates.¹ There are several organs that act as reservoirs for paraquat, including the lungs and skeletal muscles. This has resulted in paraquat being found in the urine up to three months after ingestion.¹

What is the Mechanism of Action of Bipyridyl Compounds?

Paraquat is toxic to living organisms due to a process called redox cycling. This is when a drug enters a cell, undergoes a reduction followed by reoxidation. Paraquat is reduced to form free radicals, which are then reoxidized and for a cation and a superoxide anion.

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Figure 2: Proposed mechanisms of toxicity for paraquat. 1. Intracellular redox cycling results in the oxidation of NADPH, which leads to cellular depletion, augmented by the detoxification of hydrogen peroxide from the glutathione peroxidase/reductase enzyme system to regenerate GSH, 4. 2. Generation of superoxide anion and hydroxy radicals would initiate lipid peroxidation, 3, and lead to cell death.²

Once absorbed, paraquat accumulates in the lungs and kidneys. Paraquat accumulates in the lungs and causes free radical damage in the alveolar epithelium. This is followed by edema, infiltration of inflammatory cells, and death due to anoxia.² If a person survives this initial phase, there will be proliferation of fibroblasts in the lungs, causing intensive fibrosis leading to progressive loss of lung function.² Similar damage occurs in the renal tissue, leading to reduced renal function.

What Concerns are There Other than Acute Toxicity?

There are no other major toxicological concerns for bipyridyl compounds other than those related to the acute systemic effects of exposure. Bipyridyl compounds have little to no genotoxic activity, no carcionogenic activity, no teratogenic activity, no effects on fertility, and are only fetotoxic at maternal toxic doses.²

Target Organs

Bipyridyl compounds have systemic effects, affecting several organs and systems, including²:

    • epithelium
    • cornea
    • liver
    • kidneys
    • lining of GI tract
    • lining of respiratory tract

The lungs are the primary target organ of paraquat in humans and some other animal species due to the uptake and accumulation of paraquat in type I and II alveolar epithelial cells and Clara cells.¹

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Figure 3: Clara cells in a histology of lung tissue³

What are Signs and Symptoms of Toxicity?

    • Shortly after ingestion²
      • nausea
      • vomiting
      • abdominal pain
      • diarrhea
    • 48-72 hours after exposure¹²
      • oliguria
      • jaundice
      • cough
        • productive and blood-stained
      • dyspnea
        • due to adult respiratory distress syndrome
        • bronchopneumonia
      • tachypnea
      • pulmonary edema
      • convulsions
      • coma

What Are Treatment Options?

The main treatment for bipyridyl compound poisoning is focused on prevention of absorption from the GI tract, prevention of accumulation in the lungs, use of free radical scavengers, and prevention of lung fibrosis.² Removal of the ingested poison by purging or absorption is the most effective treatment.² Treatment is largely ineffective due to the paraquat reservoirs in the body, leading to poor prognosis for critically ill patients. Once the compound has been absorbed, supportive care and keeping the patient comfortable is the only course of treatment.¹


1. Eddleston, M. Bipyridyl Herbicides. Clinical Toxicology 2000, 38, 123-128. DOI 10.1007/978-3-319-20790-2_100-1.

2.Klaassen, C.D., Ed. (2013). Casarett and Doull’s Toxicology: The Basic Science of Poisons . 8th Edition, McGraw-Hill.