Metabolic Activation of Pirfenidone Mediated by Cytochrome P450s and Sulfotransferases

Abstract

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.

Metabolic Activation and Cytotoxicity of Labetalol Hydrochloride Mediated by Sulfotransferases

“…with DCNP at a dose of 20 mg/kg for 1 h before administration of LHCl. 27 The rest of the experimental procedure was executed in accord with that mentioned above. Subsequent treatment of harvested bile samples was similar to that for cell samples.…”

“…p .) with DCNP at a dose of 20 mg/kg for 1 h before administration of LHCl . The rest of the experimental procedure was executed in accord with that mentioned above.…”

Investigating the possible mechanisms of pirfenidone to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2

“…In vitro metabolism studies with hepatic microsomes show that PFD is metabolized primarily by CYP1A2, with minor contributions from other CYP isoenzymes such as CYP2C9 and 2C19. 5-Carboxy-PFD, the main metabolite, has no or just very modest pharmacological effect [21] .…”

Evidence for Metabolic Activation of Omeprazole In Vitro and In Vivo

“…Drug-induced liver injury is a problem that draws attention, of which the generation of reactive metabolites is an important cause . For example, icaritin, pirfenidone, and aegeline can be metabolized to quinone methide intermediates and induce liver injury. − Diclofenac, acetaminophen, and amodiaquine can be metabolized to quinone imine intermediates and induce hepatotoxicity…”