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Influence of Controlled Rheumatoid Arthritis on the Action and Disposition of Verapamil: Focus on Infliximab

From the Faculty of Pharmacy and Pharmaceutical Sciences (Drs Ling, Ihejirika, and Jamali) and Faculty of Medicine (Drs Lewanczuk and Russell), University of Alberta, Edmonton, Alberta, Canada.

Active rheumatoid arthritis (RA), obesity, and old age are associated with reduced responsiveness to the calcium channel antagonist verapamil despite increased drug concentrations. The diminishing effect appears to be associated with the severity of inflammation. We examined pharmacodynamics and pharmacokinetics of verapamil in patients with controlled RA. Volunteers included RA patients in remission: 12 on infliximab, 8 on other antirheumatic therapy, and 12 healthy subjects. Verapamil plasma concentrations and selected inflammatory mediators as well as blood pressure and electrocardiographic parameters were recorded after a single 80-mg dose of verapamil. Inflammatory mediators were all below what is reported for active RA, confirming that RA was controlled. The tumor necrosis factor- concentration, however, was significantly higher in the infliximab group compared with other groups and the literature value for active RA. No significant difference was observed between groups in terms of percentage prolongation of PR interval despite a trend toward a lower response in the RA groups, the mean plasma concentrations, and the total and unbound area under the curve of verapamil. However, the slope of the S-verapamil concentration–effect curve was steeper for controls compared with the RA patients. Remission from active disease appears to restore plasma protein levels and hepatic drug metabolism activity in patients with RA, resulting in relatively normal verapamil pharmacokinetics.

Key Words: Inflammation • verapamil • remission • infliximab • rheumatoid arthritis

Address for reprints: Fakhreddin Jamali, PhD, 3118 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, AB, Canada, T6G 2N8; e-mail: fjamali{at}pharmacy.ualberta.ca.

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