Pirfenidone is small molecule with a molecular weight of 185.23 daltons whose chemical name is 5-methyl-1-phenyl-2-(1H)-pyridone. Pirfenidone has anti-fibrotic properties and has been investigated for therapeutic benefits to patients suffering from various fibrotic conditions. It is approved in Japan for treatment of idiopathic pulmonary fibrosis (IPF) under the trade name Pirespa®.
Pirfenidone has been shown to be metabolized by various isoforms of the cytochrome P450 (CYP) protein [See the Report on the Deliberation Results, Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health Labour and Welfare, Sep. 16, 2008]. Specifically, several cytochrome P450 (CYP) isoforms (CYP1A2, 2C9, 2C19, 2D6 and 2E1) were involved in the earliest stages of oxidative metabolism of pirfenidone.
Fluvoxamine belongs to a class of therapeutics known as selective serotonin reuptake inhibitors (SSRIs). The SSRIs are a group of antidepressants with similar pharmacologic effects, but with different chemical structures. Fluvoxamine has been approved for treatment of social anxiety disorder (social phobia), obsessive compulsive disorder (OCD), and has been prescribed to treat major depression, and other anxiety disorders such as panic disorder and post-traumatic stress disorder [McClellan et al., (Drugs October 2000). “Fluvoxamine An Updated Review of its Use in the Management of Adults with Anxiety Disorders”. Adis Drug Evaluation 60 (4): 925-954]. In addition to fluvoxamine, other clinically available SSRIs are citalopram, fluoxetine, paroxetine and sertraline. The elimination of these lipophilic compounds proceeds predominantly via oxidation catalysed by CYP in the liver. SSRIs have the potential for inhibition of CYP enzymes [Brosen, The pharmacogenetics of the selective serotonin reuptake inhibitors. Clin Invest 71(12):1002-1009, 1993]. Jeppesen et al. reported that fluvoxamine is a potent inhibitor of CYP1A2 in humans in vivo [Jeppesen et al., Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 51: 73-78, 1996]. Fluvoxamine has also been shown to be a very potent inhibitor of CYP1A2 in vitro [Brosen et al., Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 45:1211-1214, 1993; Rasmussen et al., Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol 39:151-159, 1995].