Metabolic Activation of Pirfenidone Mediated by Cytochrome P450s and Sulfotransferases

Pirfenidone
is approved for the treatment of idiopathic pulmonary
fibrosis. Idiosyncratic drug reactions, due to clinical application
of pirfenidone, have been documented, even along with death cases
resulting from acute liver failure. The present study aimed at the
investigation of metabolic activation of pirfenidone possibly participating
in the reported adverse reactions. Pirfenidone-derived glutathione/N-acetylcysteine (GSH/NAC) conjugates were detected in microsomal/primary
hepatocyte incubations after exposure to pirfenidone. The GSH/NAC
conjugates were also observed in bile and urine of rats given pirfenidone,
respectively. The observation of the conjugates suggests the formation
of a quinone methide intermediate derived from pirfenidone. The intermediate
was possibly generated through two pathways. First, pirfenidone was
directly metabolized to the quinone methide intermediate via dehydrogenation;
second, pirfenidone was oxidized to 5-hydroxymethyl pirfenidone, followed
by sulfation to a benzyl alcohol-sulfate derivative. The findings
facilitate the understanding of the mechanisms of pirfenidone-induced
idiosyncratic toxicity and assist medicinal chemists to minimize toxicities
in the development of new pharmaceutical agents.