Abstract
The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring 14C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and Vd(ss) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [14C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 203-211 |
| Number of pages | 9 |
| Journal | Biopharmaceutics and Drug Disposition |
| Volume | 23 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jul 2002 |
Fingerprint
Keywords
- Antifibrotic drug
- Metabolism
- Pharmacokinetics
- Pirfenidone
ASJC Scopus subject areas
- Pharmacology (medical)
- Pharmacology, Toxicology and Pharmaceutics(all)
Cite this
Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration. / Giri, Shri N.; Wang, Qingjian; Xie, Yan; Lango, Jozsef; Morin, Dexter; Margolin, Solomon B.; Buckpitt, Alan R.
In: Biopharmaceutics and Drug Disposition, Vol. 23, No. 5, 07.2002, p. 203-211.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration
AU - Giri, Shri N.
AU - Wang, Qingjian
AU - Xie, Yan
AU - Lango, Jozsef
AU - Morin, Dexter
AU - Margolin, Solomon B.
AU - Buckpitt, Alan R
PY - 2002/7
Y1 - 2002/7
N2 - The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring 14C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and Vd(ss) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [14C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.
AB - The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring 14C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and Vd(ss) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [14C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.
KW - Antifibrotic drug
KW - Metabolism
KW - Pharmacokinetics
KW - Pirfenidone
UR - http://www.scopus.com/inward/record.url?scp=0036647071&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036647071&partnerID=8YFLogxK
U2 - 10.1002/bdd.311
DO - 10.1002/bdd.311
M3 - Article
C2 - 12116052
AN - SCOPUS:0036647071
VL - 23
SP - 203
EP - 211
JO - Biopharmaceutics and Drug Disposition
JF - Biopharmaceutics and Drug Disposition
SN - 0142-2782
IS - 5
ER -