Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration

Giri, Shri N.; Wang, Qingjian; Xie, Yan; Langó, József; Morin, Dexter; Margolin, Solomon B.; Buckpitt, Alan R.

doi:10.1002/bdd.311

Cited by 43 publications

(60 citation statements)

References 14 publications

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“…Our results in rats suggest PFD also has no other adverse effects within the dose range observed that was consistent with the previous reports in animals and humans (Mansoor et al, 1999;Gahl et al, 2002;Giri et al, 2002;Nagai et al, 2002). Plasma PFD concentrations did not seem to relate to differences in therapeutic effects similar to the previous reports from patients and mice with PFD (Giri et al, 2002;Nagai et al, 2002). We think the findings that a rat in the 80 mg/kg PFD group died 24 h after OA injection was not drug-related.…”

supporting

confidence: 93%

Protection of Pirfenidone against an Early Phase of Oleic Acid-Induced Acute Lung Injury in Rats

Mei

Yao²,

Zhu³

et al. 2004

J Pharmacol Exp Ther

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The potential role of PFD [5-methyl-L-phenyl-2-(1H)-pyridone], an antifibrotic compound with anti-inflammatory effects, in several models of acute lung injury (ALI) has gained increasing attention; however, the protective effect of PFD in oleic acid (OA)-induced ALI remains unknown. We hypothesized that PFD protects from OA-induced ALI in rats, and we hoped to obtain the optimum preclinical conditions with PFD in ALI. SpragueDawley rats were randomized into five groups (five rats per group): normal control group, OA-treated group (0.15 ml/kg), and three PFD-treated groups (20, 40, and 80 mg/kg p.o., respectively). Arterial blood gases, lung wet/dry weight ratio, and postmortem histological changes were determined 0.5, 1, 2, 6, and 24 h after OA challenge. Electron spin resonance spectroscopy was used for free radical detection and measurement. Experiments were examined based on the orthogonal test L4 (4 2 ) setting two factors (PFD dose and PFD valid time) with four different levels. The results of the orthogonal test showed that the sequence of effect of PFD was 0.5 h (oxygen radicals), 1 h (histological changes), 2 h (lung edema), and 6 h (partial pressure of oxygen) after OA challenge, and 40 mg/kg PFD was the most effective dose in this study. We conclude that PFD protects against OA-induced ALI in rats. The mechanism of these protective effects partly involves decrease of oxygen radicals. The data of this study proves that the orthogonal test will be a powerful method to help obtain the optimum experimental conditions with PFD in ALI in the future.

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supporting

confidence: 93%

Protection of Pirfenidone against an Early Phase of Oleic Acid-Induced Acute Lung Injury in Rats

Mei

Yao²,

Zhu³

et al. 2004

J Pharmacol Exp Ther

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“…Similarly rapid absorption is observed in nonclinical species [32,33] and a radiometric study in mice demonstrates broad distribution in well perfused tissues including liver, kidney, heart and lung [34].…”

Section: Review: Antifibrotic Activities Of Pirfenidonementioning

confidence: 58%

“…In humans and nonclinical species, pirfenidone is extensively metabolised. The principal site of metabolism is the 5-methyl position of the pyridone ring, resulting in stepwise formation of 5-hydroxymethyl pirfenidone and a 5-carboxcylic acid metabolite [31,34]. The 5-carboxcylic acid metabolite accounts for 95% of the recovered dose in healthy older adults [31].…”

Section: Review: Antifibrotic Activities Of Pirfenidonementioning

confidence: 99%

Antifibrotic activities of pirfenidone in animal models

Schaefer¹,

Ruhrmund²,

Lin³

et al. 2011

European Respiratory Review

366

287

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Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with modulation of cytokines and growth factors, with the most commonly reported effect being reduction of transforming growth factor-b. The consistent antifibrotic activity of pirfenidone in a broad array of animal models provides a strong preclinical rationale for the clinical characterisation of pirfenidone in pulmonary fibrosis and, potentially, other conditions with a significant fibrotic component. KEYWORDS: Animal model, antifibrotic, fibrosis, idiopathic pulmonary fibrosis, pirfenidone F ibrosis, the dysregulated deposition of extracellular matrix (ECM) with progressive destruction of normal tissue, is a primary or contributing factor in chronic disease states in several organs. Pulmonary fibrosis is associated with numerous diffuse parenchymal lung diseases, of which the most common are idiopathic pulmonary fibrosis (IPF) and sarcoidosis [1]. Cardiac fibrosis is associated with chronic heart failure, atrial fibrillation, and cardiac remodelling following acute myocardial infarction [2,3]. Renal fibrosis is associated with multiple forms of chronic kidney disease and correlates with impairment of kidney function [4,5]. Hepatic fibrosis is associated with chronic hepatitis B and C viral infections and nonalcoholic steatohepatitis [6]. Each of these conditions represents a significant unmet medical need, warranting significant research and clinical study into treatment for fibrotic disease.Pirfenidone (Esbriet1, Pirespa1) is an orally active small molecule comprising a modified phenyl pyridone ( fig. 1). The compound exhibits well documented antifibrotic and anti-inflammatory activities in a variety of animal and cellbased models, although its molecular target has not been elucidated. Pirfenidone was initially identified as having anti-inflammatory activity in animal models and evaluated for use as an antiinflammatory drug [7,8]. However, the unexpected identification of antifibrotic effects in animals treated with pirfenidone redefined the interest in the compound [9]. Subsequently, pirfenidone has been shown to attenuate fibrosis in numerous animal models, including fibrosis of the lung, liver, heart and kidney.The most extensive clinical studies of pirfenidone are for treatment of IPF, a chronic interstitial lung disease characterised by the unregulated deposition of ECM leading to the unremitting destruction of normal lung. Patients diagnosed with IPF typically experience progressive pulmonary insufficiency, and most die of respiratory failure. The estimated median survival upon diagnosis is approximately ...

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“…The thiazolidinedione compounds and certain prostaglan- dins have been used to demonstrate that activation of PPAR␥ inhibits collagen synthesis (18) and fibrosis in lung (14,15,19,57), kidney (8,9,58), liver (10,11,33,36,59), cardiac fibroblasts (60), and skin (61). The issue of endogenous ligand for PPAR␥ in cells has been controversial.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor γ Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression

Farmer

Smith

2007

Journal of Biological Chemistry

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Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration

Cited by 43 publications

References 14 publications

Protection of Pirfenidone against an Early Phase of Oleic Acid-Induced Acute Lung Injury in Rats

Protection of Pirfenidone against an Early Phase of Oleic Acid-Induced Acute Lung Injury in Rats

Antifibrotic activities of pirfenidone in animal models

Peroxisome Proliferator-activated Receptor γ Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression

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