Metabolism and disposition of phenazopyridine in rat

Abstract

1. The blood profile, tissue distribution, biliary and urinary excretion, and metabolism of 14C-phenazopyridine (PAP) was studied in male Wistar rats. 2. Based on the blood profile of 14C the absorption of PAP from the gastrointestinal tract was rapid; the t1/2 of elimination was 7.35 h. 3. Biliary excretion was a major route of elimination with 40.7% dose excreted by this route in bile duct-cannulated rats over the 0-8 h period. The predominant metabolite was conjugated 4'-hydroxy-PAP. 4. Liver and kidney showed the highest tissue levels of PAP-derived 14C, and significant covalent binding was found in these two tissues. 5. The major urinary metabolite of PAP was 4-acetylaminophenol (NAPA) followed in order by 5,4'-dihydroxy-PAP, 5-hydroxy-PAP, 4'-hydroxy-PAP and 2'-hydroxy-PAP; unchanged PAP accounted for < 1% dose. 6. Doubling the dose of PAP to 200 mg/kg caused a proportionate decrease in urinary NAPA excretion and an increase in 5-hydroxy-PAP.

Presumptive hepatotoxicity and rhabdomyolysis secondary to phenazopyridine toxicity in a dog

“…Jaundice, liver function test abnormalities, 15 and hypersensitivity hepatitis 16 due to PAP have occurred in humans. The exact mechanism of hepatotoxicity in PAP ingestion is unknown but is possibly similar to acetaminophen (APAP), because APAP is a toxic metabolite of PAP 3–6 . In acetaminophen‐induced hepatotoxicity, the parent compound overwhelms the metabolic pathways resulting in production of toxic metabolites that cause oxidative damage to the hepatocytes 22,23 .…”

“…Treatment of PAP toxicosis recommended by the APCC is based on the approach to acetaminophen toxicity 22,23,27 . Both PAP and acetaminophen share similar metabolic pathways resulting in the same metabolite responsible for causing toxicity 3–6 . Treatment may include gastric decontamination via induction of emesis or gastric lavage and activated charcoal administration (1–3 g/kg) within 1–2 hours of ingestion in an asymptomatic patient 28 .…”

“…APAP, which is the commonly used drug acetaminophen, is the major urinary metabolite of PAP in most species (NAPA in Figure 2). 3–6 The analogous metabolites may explain why both PAP and acetaminophen have similar toxic adverse effects in animals, such as methemoglobinemia (MetHb) and hepatoxicity 7…”

“… Metabolic pathways of phenazopyridine (PAP), and major routes of excretion 4 . NAPA (or APAP), which is the commonly used drug acetaminophen, is the major urinary metabolite of PAP in most species.…”

Phenazopyridine abuse presenting with acute kidney injury, hemolytic anaemia and jaundice

“…It is primarily eliminated through the kidneys and has a blood halflife of 7.35 hours in individuals with normal renal function [1]. The most common side side-effects of phenazopyridine are orange discoloration of the urine and diarrhoea.…”