The effect of different calcium antagonists and a calcium agonist on the metabolism of propranolol by isolated rat hepatocytes

Abstract

The influence of the dihydropyridine calcium entry blockers nicardipine, amlodipine, nifedipine, isradipine and of the dihydropyridine calcium entry promotor BAY K 8644 on the disappearance rate of propranolol by isolated rat hepatocytes was compared to the effect of diltiazem and verapamil, two non-dihydropyridine calcium channel blockers and known inhibitors of hepatic cytochrome P450 mixed function oxidases. All compounds dose-dependently inhibited the disappearance rate of propranolol. Nicardipine and isradipine were more potent in inhibiting the disappearance rate of propranolol than the other dihydropyridines and than diltiazem and verapamil. The inhibitory effect of nicardipine on the disappearance rate of propranolol was not stereoselective and was not influenced by age.

Amlodipine Inhibits Rat Microsomal Cytochrome P450-Mediated Drug Biotransformation

“…For example, although nifedipine appears to have little effect on the elimination of CyA in adult renal transplant patients, 8,9 it has been reported to inhibit CYA metabolism in pediatric renal transplant patients. 23 The results of the present study, in addition to the inhibition of propranolol metabolism (CYP2D-mediated) by amlodipine reported by Vercruysse et al 4 …”

“…However, such an argument may not always hold for calcium channel blocking drugs. For example, Vercruysse et al 4 reported that the metabolism of propranolol by isolated rat hepatocytes was reduced by 50% when nifedipine was added to a concentration of 30 mM. Although this concentration greatly exceeds plasma concentrations observed in humans or rats, nifedipine causes significant inhibition of propranolol metabolism in vivo in rats.…”

“…[7][8][9] As far as amlodipine is concerned, the disappearance rate of propranolol in isolated rat hepatocytes was reduced by 30% when amlodipine is present at equimolar concentrations to that of propranolol. 4 However, the degree of inhibition by amlodipine was much less than for other calcium channel antagonists, such as diltiazem (46% inhibition) and nifedipine (50% inhibition), at similiar concentrations. 4 In controlled human studies, amlodipine had no effect on the metabolism of CyA, benazepril, or digoxin.…”

“…4 However, the degree of inhibition by amlodipine was much less than for other calcium channel antagonists, such as diltiazem (46% inhibition) and nifedipine (50% inhibition), at similiar concentrations. 4 In controlled human studies, amlodipine had no effect on the metabolism of CyA, benazepril, or digoxin. 10-12 To date, no drug interactions have been reported that can be attributed to cytochrome P-450 inhibition by amlodipine, but this drug has not been in widespread clinical use for an extended time.…”

“…Nifedipine, diltiazem, and verapamil have been shown to inhibit the cytochrome P450-mediated in vitro metabolism of a number of compounds, including propranolol, aminopyrine, and cyclosporine (CyA). [1][2][3][4] Verapamil and diltiazem have also been reported to decrease the clearance of drugs in vivo, 5-7 but nifedipine appears to have little or no effect on the in vivo elimination of drugs. [7][8][9] As far as amlodipine is concerned, the disappearance rate of propranolol in isolated rat hepatocytes was reduced by 30% when amlodipine is present at equimolar concentrations to that of propranolol.…”