RT Journal Article
SR Electronic
T1 Rofecoxib Is a Potent, Metabolism-Dependent Inhibitor of CYP1A2: Implications for in Vitro Prediction of Drug Interactions
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2091
OP 2096
DO 10.1124/dmd.106.011965
VO 34
IS 12
A1 Marjo J. Karjalainen
A1 Pertti J. Neuvonen
A1 Janne T. Backman
YR 2006
UL http://dmd.aspetjournals.org/content/34/12/2091.abstract
AB Rofecoxib was recently found to greatly increase plasma concentrations of the CYP1A2 substrate drug tizanidine in humans, but there are no published in vitro studies on the CYP1A2-inhibiting effects of rofecoxib. Our objective was to investigate whether rofecoxib is a direct-acting or metabolism-dependent inhibitor of CYP1A2 in vitro. The effect of rofecoxib on the O-deethylation of phenacetin (20 μM) was studied using human liver microsomes. The effect of preincubation time on the inhibitory potential of rofecoxib was also studied, and the inhibitor concentration that supports half the maximal rate of inactivation (KI) and the maximal rate of inactivation (kinact) were determined. Rofecoxib moderately inhibited phenacetin O-deethylation (IC50 23.0 μM), and a 30-min preincubation with microsomes and NADPH considerably increased its inhibitory effect (IC50 4.2 μM). Inactivation of CYP1A2 by rofecoxib required NADPH, and was characterized by a KI of 4.8 μM and a kinact of 0.07 min–1. Glutathione, superoxide dismutase, mannitol, or dialysis could not reverse the inactivation of CYP1A2 caused by rofecoxib. Fluvoxamine decreased the rofecoxib-caused inactivation of CYP1A2 in a concentration-dependent manner. In conclusion, rofecoxib is a potent, metabolism-dependent inhibitor of CYP1A2, a cytochrome P450 form contributing to rofecoxib metabolism. The results provide a mechanistic explanation for the interactions of rofecoxib with CYP1A2 substrates and may partially explain its nonlinear pharmacokinetics. The American Society for Pharmacology and Experimental Therapeutics