Despite increased plasma concentration, inflammation reduces potency of calcium channel antagonists due to lower binding to the rat heart

Abstract

1 Rheumatoid arthritis reduces verapamil oral clearance thereby increases plasma concentration of the drug. This coincides with reduced drug effects through an unknown mechanism. 2 The effect of interferon-induced acute inflammation on the pharmacokinetics and electrocardiogram of verapamil (20 mg kg À1 , p.o.) and nifedipine (0.1 mg kg À1 , i.v.) was studied in SpragueDawley rats. 3 The effect of both acute and chronic inflammation on radioligand binding to cardiac L-type calcium channels was also investigated. 4 Acute inflammation resulted in increased plasma concentration of verapamil but had no effect on that of nifedipine. Verapamil binding to plasma proteins was unaffected. 5 As has been reported for humans, the increased verapamil concentration coincided with a reduction in the degree to which PR interval is prolonged by the drug. The effect of nifedipine on PR interval was also reduced by inflammation. 6 Maximum binding of 3 H-nitrendipine to cardiac cell membrane was significantly reduced from 63.272.5 fmol mg À1 protein in controls to 46.472.0 in acute inflammation and from 66.872.2 fmol mg À1 protein in controls to 42.272.0 in chronic inflammation. 7 Incubation of the normal cardiac cell membranes with 100 and 1000 pg ml À1 of rat tissue necrosis factor-a did not influence the binding indices to the calcium channels. 8 Our data suggest that the reduced calcium channel responsiveness is because of altered binding to channels.

Effect of Early Phase Adjuvant Arthritis on Hepatic P450 Enzymes and Pharmacokinetics of Verapamil: An Alternative Approach to the Use of an Animal Model of Inflammation for Pharmacokinetic Studies

“…Pre-AA significantly elevated C max and AUC 0 -4 h for both enantiomers of verapamil (Table 1). Similar effects have been observed in acute inflammation (Laethem et al, 1994;Sattari et al, 2003) and confirm that pre-AA is a suitable alternative model of inflammation for pharmacokinetic studies. It is of value to mention that, following oral administration to inflamed rats, a greater extent of variability was observed in the plasma verapamil concentrations (Fig.…”

“…Other models of inflammation have shown varying effect on protein binding of verapamil. Endotoxininduced inflammation reduces unbound fraction of verapamil (Laethem et al, 1994), whereas interferon ␣-2a-induced inflammation does not significantly affect protein binding (Sattari et al, 2003). This suggests that altered protein levels may be dependent on the type of inflammation.…”

“…and i.v. pharmacokinetics of verapamil, a drug with well known efficient hepatic metabolism (Laethem et al, 1994;Mayo et al, 2000;Sattari et al, 2003). Since decreased clearance of drugs during inflammatory conditions may also be due to increased binding to plasma proteins secondary to an elevation of acute-phase protein ␣ 1 -acid glycoprotein (AAG) (Belpaire et al, 1982), we also studied the effect of pre-AA on the protein binding of verapamil.…”

Altered Drug Metabolism and Transport in Pathophysiological Conditions

“…Down-regulation of hepatic P-gp in AA rats was attributed to elevated levels of cytokines such as TNF-and IL-6 but not IL-1 (Philippe et al, 1997). Similarly, increased plasma concentrations of drugs in AA rats correlated with increased serum TNF-level (Sattari et al, 2003). Several in vitro and in vivo studies have shown up-regulation of NF-κB in RA and osteoarthritis (Handel et al, 1995;Mor et al, 2005).…”

“…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).…”