PT  - JOURNAL ARTICLE
AU  - Deborah A. Nicoll-Griffith
AU  - Jose M. Silva
AU  - Nathalie Chauret
AU  - Stephen Day
AU  - Yves Leblanc
AU  - Patrick Roy
AU  - James A. Yergey
AU  - Rakesh Dixit
AU  - Darryl Patrick
TI  - Application of Rat Hepatocyte Culture to Predict in Vivo Metabolic Auto-Induction: Studies with DFP, a Cyclooxygenase-2 Inhibitor
DP  - 2001 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 159--165
VI  - 29
IP  - 2
4099  - http://dmd.aspetjournals.org/content/29/2/159.short
4100  - http://dmd.aspetjournals.org/content/29/2/159.full
SO  - Drug Metab Dispos2001 Feb 01; 29
AB  - The drug candidate DFP [5,5-dimethyl-3-(2-isopropoxy)-4-(4-methanesulfonylphenyl)-2(5H)-furanone] is a selective cyclooxygenase-2 inhibitor under evaluation for analgesic and anti-inflammatory therapy. The in vitro metabolic pathways (rat microsomes) involve hydroxylation of the isopropyl side chain at either of two positions, the methyl or the methine, thus producing a hydroxylated metabolite (DFHP) or a dealkylated metabolite (DFH). DFH formation was the major pathway. Using hepatic microsomes from rats treated with agents that induce specific CYP isozymes, it was shown that the dexamethasone-inducible rat CYP3A isozyme(s) play a major role in DFH formation. The roles of CYP3A1 and -3A2 were confirmed with genetically engineered rat CYP enzymes. The potential for induction of rat CYP3A by DFP was evaluated by incubating DFP in rat hepatocyte cultures and measuring the CYP3A levels. Both CYP3A immunoreactive protein and enzyme activity were induced in a dose-dependent manner. The induction was confirmed in vivo by dosing rats with DFP at 100 mg/kg for 4 days. Microsomes prepared from the excised livers showed that DFP gave ∼55% of the induction observed with dexamethasone, as determined by Western blot. In vitro metabolic auto-induction of DFP was assessed by measuring the metabolism of DFP in hepatocytes treated with DFP. DFH formation was significantly enhanced in the DFP-treated cells. In vivo, treating rats with DFP at doses of 10 to 100 mg/(kg·day) for 13 weeks indicated that DFP induced its own metabolism. The Cmax and plasma drug area under the curve values during the thirteenth week were significantly lower than that on the first day, and the effect was dose-dependent. The American Society for Pharmacology and Experimental Therapeutics