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Pirfenidone 5-hydroxylation is mainly catalysed by CYP1A2 and partly catalysed by CYP2C19 and CYP2D6 in the human liver.
- Source :
-
Xenobiotica . Dec 021, Vol. 51 Issue 12, p1352-1359. 8p. - Publication Year :
- 2021
-
Abstract
- Pirfenidone is a first-line drug for the treatment of idiopathic pulmonary fibrosis. The primary metabolic pathways of pirfenidone in humans are 5-hydroxylation and subsequent oxidation to 5-carboxylpirfenidone. The aims of this study were to determine the cytochrome P450 isoforms responsible for pirfenidone 5-hydroxylation and to evaluate their contributions in human liver microsomes (HLM). Among the recombinant P450 isoforms, CYP1A2, CYP2D6, CYP2C19, CYP2A6, and CYP2B6 were shown to catalyse the 5-hydroxylation of pirfenidone. Pirfenidone 5-hydroxylase activity by HLM was inhibited by α-naphthoflavone (by 45%), 8-methoxypsolaren (by 84%), tranylcypromine (by 53%), and quinidine (by 15%), which are CYP1A2, CYP1A2/CYP2A6/CYP2C19, CYP2A6/CYP2C19, and CYP2D6 inhibitors, respectively. In 17 individual HLM donors, pirfenidone 5-hydroxylase activity was significantly correlated with phenacetin O-deethylase (r = 0.89, P < 0.001) and S-mephenytoin 4'-hydroxylase activities (r = 0.51, P < 0.05), which are CYP1A2 and CYP2C19 marker activities, respectively. By using the relative activity factors, the contributions of CYP1A2, CYP2C19, and CYP2D6 to pirfenidone 5-hydroxylation in the human liver were 72.8%, 11.8%, and 8.9%, respectively. In conclusion, we clearly demonstrated the predominant P450 involved in pirfenidone 5-hydroxylation in the human liver is CYP1A2, with CYP2C19 and CYP2D6 playing a minor role. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00498254
- Volume :
- 51
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- Xenobiotica
- Publication Type :
- Academic Journal
- Accession number :
- 155030036
- Full Text :
- https://doi.org/10.1080/00498254.2021.2007553