The effect of infliximab on hepatic cytochrome P450 and pharmacokinetics of verapamil in rats with pre-adjuvant arthritis: a drug-disease and drug-drug interaction

Abstract

Inflammatory conditions result in increased concentration but reduced potency of some cardiovascular drugs. This is associated with increased levels of pro-inflammatory mediators. Infliximab reduces pro-inflammatory mediators and reverses the diminishing effect of inflammation on response in the rat. We suggested that infliximab treatment would also reverse the effects of inflammation on drug metabolism and clearance. We examined hepatic cytochrome P450 content and the pharmacokinetics of verapamil in pre-adjuvant arthritic rats treated with infliximab. Pre-adjuvant arthritis was induced in male Sprague-Dawley rats with a tail base injection of Mycobacterium butyricum. Animals were monitored for symptoms of arthritis, serum nitrite and C-reactive protein. On day 6, rats were administered with single s.c. doses of infliximab (10 mg/kg). On day 14, a single i.v. dose of racemic verapamil (2 mg/kg) was administered, and S- and R-verapamil concentrations were determined by high performance liquid chromatography. Hepatic cytochrome P450 content and verapamil protein binding were also measured. Serum nitrite levels were significantly elevated in pre-adjuvant arthritis. Infliximab did not affect mean nitrite concentrations but there was a significant correlation between nitrite and S-verapamil concentrations as well as cytochrome P450, CYP3A, and CYP1A contents. Infliximab increased cytochrome P450 enzymes content that had been diminished by pre-adjuvant arthritis but had no significant effect on verapamil protein binding. Infliximab partially restores hepatic cytochrome P450 enzyme contents. The effect of infliximab on the mean verapamil clearance was not significantly affected due, likely, to the lack of effect on plasma protein binding.