2,3,6-triaminopyridine, a metabolite of the urinary tract analgesic phenazopyridine, causes muscle necrosis and renal damage in rats

Abstract

Some aromatic polyamines form very stable free radicals and readily undergo autoxidation with concomitant formation of ‘active oxygen’ species. These substances cause necrosis of striated muscle in rats, and it has been suggested that this is due to free radical formation and disruption of energy production through their oxidation via the cytochrome c/cytochrome oxidase system of mitochondria. 2,3,6‐Triaminopyridine, which is structurally related to the myotoxic amines and likewise undergoes autoxidation and disrupts mitochondrial metabolism, is a metabolite of the widely used urinary analgesic phenazopyridine. When administered to rats, triaminopyridine caused extensive necrosis of skeletal muscle and a lesser degree of damage to heart muscle. It also induced vacuolation and necrosis of distal tubules of the kidney, associated with tubular dilatation and cast formation. Both muscle damage and renal tubular necrosis have been reported following use or abuse of phenazopyridine, and it is likely that triaminopyridine is responsible for both of these effects. © 1998 John Wiley & Sons, Ltd.

A screen for protective drugs against delayed hypoxic injury

“…However, the underlying mechanism of phenazopyridine action is not well known. 2,3,6-triaminopyridine, a metabolite of phenazopyridine, causes muscle necrosis and renal damage in rats and promotes generation of superoxide radical and hydrogen peroxide [27,28]. Whether phenazopyridine inhibits delayed hypoxic injury through its metabolite, 2,3,6-triaminopyridine, by regulating generation of reactive oxygen species remains to be determined.…”

Acute Renal Failure and Jaundice without Methemoglobinemia in a Patient with Phenazopyridine Overdose: Case Report and Review of the Literature

“…Direct toxic damage is most commonly observed on biopsies [2, 3]. Likewise, animal studies of triaminopyridine have shown vacuolization and necrosis of the distal tubules [15]. Certainly in this case direct toxicity appears to be the most likely cause of his renal failure, since neither hemolytic anemia nor methemoglobinemia were present.…”

Presumptive hepatotoxicity and rhabdomyolysis secondary to phenazopyridine toxicity in a dog

“…PAP in animals may cause signs of gastroenteritis (vomiting, diarrhea, or abdominal pain), hemolytic anemia, MetHb, acute kidney failure, and hepatotoxicity 1,17,18 . PAP has also been shown to cause muscle damage 19 and keratoconjunctivitis sicca 20 experimentally in animal models.…”

“…Humans taking PAP have described muscular pains associated with increased plasma activities of CK, lactate dehydrogenase, and aldolase, indicative of muscle injury 11 . The metabolite 2,3,6‐triaminopyridine caused extensive necrosis of skeletal muscle and to a lesser degree damage to heart muscle in rats secondary to the generation of superoxidative free radicals, which caused oxidative damage to the cells 19 . In experimental canine PAP toxicity studies, sensory and motor paralysis of hind limbs occurred with dark edematous hind limb muscles seen at necropsy at total doses of 1 g/kg administered IV 18…”

“…Kidney toxicity was not evident in the present case; however, acute kidney failure has been reported with large doses or prolonged use of PAP in humans 11–14 and PAP has been shown to cause toxic degeneration of renal collecting tubules in dogs and cats 1,17 . The metabolites aniline, p ‐aminophenol and 2,3,6‐triaminopyridine have been shown to be nephrotoxic 19 …”