Disease-drug interaction: Reduced response to propranolol despite increased concentration in the rat with...

Inflammatory conditions reduce clearance, hence increase plasma concentration of drugs such as propranolol that are efficiently cleared by the liver. The therapeutic consequences of this increased plasma drug concentration is mainly unknown. However, for sotalol, another beta-adrenergic antagonist, inflammation causes reduced potency. Sotalol, however, is renally cleared; hence, its clearance is unaffected by inflammation. We examined if the inflammation-induced increased plasma propranolol concentration compensates for the reduced responsiveness. A modified lead I ECG was used to record PR interval and heart rate (HR). ECG was monitored following oral administration of 3, 5, 10, 15, 20, 25, and 30 mg/kg propranolol to both control and adjuvant arthritis (AA) rats. To confirm altered pharmacokinetics, single 25 mg/kg doses of propranolol were administered to both AA and control rats, with an inserted cannula in their right jugular vein for serial blood sampling. As expected, AA caused a significant reduction in the propranolol oral clearance and subsequently substantial increases in plasma total and unbound drug concentration. Interestingly, however, despite the elevated propranolol concentrations, the effect on HR remained unchanged and the prolongation of PR interval was significantly reduced in AA compared with control rats. The reduced sensitivity to propranolol in AA rats is suggestive of altered beta-adrenergic receptors function.