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Pharmacokinetics, tissue distribution, plasma protein binding, and metabolism study of mefunidone, a novel pirfenidone derivative
Author(s) -
Han Xuhua,
Li Fang,
Wen Zhou,
Ma Yuehui,
Wang Lei,
Cheng Zeneng
Publication year - 2019
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.13078
Subject(s) - in vivo , pharmacokinetics , bioavailability , microsome , chemistry , pharmacology , hydroxylation , metabolism , volume of distribution , in vitro , enzyme , biochemistry , biology , microbiology and biotechnology
Summary Mefunidone ( MFD ), a novel derivation of pirfenidone ( PFD ), exhibits promising anti‐renal fibrosis activity. To avoid early development failures and attrition in clinical phase 1, an evaluation of the preclinical pharmacokinetic ( PK ) properties of MFD was conducted in this study. The absolute bioavailability was evaluated in Sprague Dawley rats and cynomolgus monkeys, who received an intragastric or intravenous administration at the dose of 31.25 mg/kg and 10 mg/kg, respectively. Tissue distribution and plasma protein binding studies were performed to evaluate the distribution characteristics of MFD . The enzymes involved in the metabolism of MFD were assayed by calculating the inhibition rate using the in vitro incubation system of human liver microsomes. The metabolic pathway of MFD was also examined in the in vitro incubation system as well as in rats in vivo . The results revealed satisfactory absorption of MFD in vivo, with an absolute bioavailability of MFD in rats and monkeys of approximately 77.2% and 70.0%, respectively. MFD was rapidly distributed to all tissues and was highly concentrated in the kidney, which was the target organ of MFD . The plasma protein binding rates in rat, monkey, and human plasma were 36.40%–41.68%, 30.88%–63.92%, and 37.75%–57.77%, respectively. MFD was primarily metabolized by the enzymes CYP 3A4, CYP 2C9, and CYP 2C8. The metabolic pathway of MFD is nitrogen demethylation of the pyridine ring of the MFD nucleus, hydroxylation of the aromatic ring, and demethylation of the piperazine ring. In conclusion, MFD exhibited good PK properties in the initial preclinical PK study. The results strongly support further research to investigate the potential of MFD as a clinical anti‐renal fibrosis drug.