Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis

Aims Inflammation reduces hepatic clearance of many drugs with unknown ther apeutic consequences. This study was carried out to examine the effect of r heumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of ve rapamil. Methods Eight RA patients were age- and sex-matched with eight healthy volu nteers. The disease severity was assessed, and ECG, blood pressure and vera pamil enantiomers concentrations were measured for 12 h post 80 mg oral ver apamil. Serum interleukin-6 (IL-6) and nitrite (NO2-) were measured in pred ose samples. Results IL-6 and NO2- concentrations were significantly increased in parall el with disease severity. Oral clearance of both S- and R-verapamil was sig nificantly decreased by RA. While the unbound fraction of S- and R-verapami l decreased by 5 and 7-fold, respectively, the unbound AUC remained unchang ed for the more potent enantiomer, S-verapamil. AUC of norverapamil enantio mers was increased 2-3-fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR-interval was significantly reduced by o ne fold and the effect on the heart rate and blood pressure did not increas e. Conclusions RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic bloo d flow. A significant decrease in dromotropic effect, despite increased ser um drug concentrations, may be attributed to receptor down regulation cause d by pro-inflammatory cytokines and/or NO.