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

Abstract

Aims In¯ammation 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 signi®cantly increased in parallel with disease severity. Oral clearance of both S-and R-verapamil was signi®cantly 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 signi®cantly 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¯ow. A signi®cant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro-in¯ammatory cytokines and/or NO.

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

“…As described previously, a systemic inflammatory response has been shown to be associated with the repression of Cyp3a activity (Shedlofsky et al, 1994;Mayo et al, 2000;Frye et al, 2002). In order to determine whether the presence of malignancy induced a systemic inflammatory response, the mRNA expression of the hepatic acute phase reactants, serum amyloid protein (Sap) and metallothionein were measured in tumour-bearing mice compared with controls.…”

Changes in expression of hepatic cytochrome P450 subfamily enzymes during development of adjuvant-induced arthritis in rats

“…Several reports have suggested that the pharmacokinetics of drugs such as atorvastatin (Kruger et al, 2009), erythromycin (Rivory et al, 2002), verapamil (Mayo et al, 2000) and propranolol (Ling and Jamali, 2005), which are metabolized by CYP3A subfamily enzymes, are altered in the patients with inflammatory diseases. For example, the serum concentrations of antihypertensive drugs, such as verapamil and propranolol, are higher in patients with rheumatoid arthritis than in healthy subjects or with mild disease (Mayo et al, 2000;Schneider et al, 1981).…”

“…For example, the serum concentrations of antihypertensive drugs, such as verapamil and propranolol, are higher in patients with rheumatoid arthritis than in healthy subjects or with mild disease (Mayo et al, 2000;Schneider et al, 1981). Likewise, decreases in the clearance of these antihypertensive drugs have been reported in rats with adjuvant-induced arthritis (Guirguis and Jamali, 2003;Ling and Jamali, 2005).…”

Altered Drug Metabolism and Transport in Pathophysiological Conditions

“…E.g. despite of very high plasma concentrations of the calcium channel blocker, verapmil, or potassium channel antagonists, sotalol or propranolol; no change in the PD was seen in inflamed animals (Guirguis & Jamali, 2003;Kulmatycki et al, 2001;Mayo et al, 2000). The authors concluded this to be due to altered receptor-functioning or receptor-ligand binding exhibited by inflammation.…”

“…Based on these early observations, recent studies have also shown altered PK of methotrexate, T-5557 (novel anti-inflammatory agent) and doxorubicin in AA animals (Achira et al, 2002a(Achira et al, , 2002b2002d). Although, a significant increase in the plasma concentrations of verapamil in rats and humans with underlying arthritis were reported, there were no changes in the PD of verapamil (prolongation of PR interval) (Mayo et al, 2000;Sattari et al, 2003). This discrepancy was then attributed to a decrease in the receptorligand affinity in inflammation (Laporte et al, 1998;Shore et al, 1997).…”