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Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis
Author(s) -
Mayo Patrick R.,
Skeith Kenneth,
Russell Anthony S.,
Jamali Fakhreddin
Publication year - 2000
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2000.00314.x
Subject(s) - verapamil , rheumatoid arthritis , pharmacokinetics , medicine , pharmacology , pharmacodynamics , endocrinology , calcium
Aims Inflammation reduces hepatic clearance of many drugs with unknown therapeutic consequences. This study was carried out to examine the effect of rheumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of verapamil. Methods Eight RA patients were age‐ and sex‐matched with eight healthy volunteers. The disease severity was assessed, and ECG, blood pressure and verapamil enantiomers concentrations were measured for 12 h post 80 mg oral verapamil. Serum interleukin‐6 (IL‐6) and nitrite (NO 2 – ) were measured in predose samples. Results IL‐6 and NO 2 – concentrations were significantly increased in parallel with disease severity. Oral clearance of both S‐ and R‐verapamil was significantly decreased by RA. While the unbound fraction of S‐ and R‐verapamil decreased by 5 and 7‐fold, respectively, the unbound AUC remained unchanged for the more potent enantiomer, S‐verapamil. AUC of norverapamil enantiomers was increased 2–3‐fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR‐interval was significantly reduced by one fold and the effect on the heart rate and blood pressure did not increase. Conclusions RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic blood flow. A significant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro‐inflammatory cytokines and/or NO.