EFFECTS OF CALCIUM-CHANNEL BLOCKERS ON THE PHARMACOKINETICS OF PROPRANOLOL STEREOISOMERS

Diltiazem and verapamil inhibit oxidative drug metabolism both in vivo and in vitro. We compared their effects on the stereoselective pharmacokinetics and protein binding of propranolol in 12 subjects. After 6 days of coadministration with racemic propranolol, diltiazem caused decreases of 27% and 24% in d‐propranolol and 1‐propranolol oral clearances, respectively (p < 0.05 versus control). With verapamil, d‐propranolol oral clearance decreased 32% (p < 0.05), and 1‐propranolol oral clearance decreased 26% (p < 0.05). The unbound fraction of d‐propranolol was higher than that of 1‐propranolol (p < 0.05), but the protein binding was not altered by diltiazem or verapamil. Both drugs therefore decreased the unbound oral clearance of each propranolol enantiomer (p < 0.05). Verapamil caused a stereoselective effect and increased the d/1 ratio of propranolol serum concentrations (p < 0.05) and decreased the d/1 ratio of oral clearance (p < 0.05). Clinical Pharmacology and Therapeutics (1990) 47, 584–591; doi: © 1990 American Society for Clinical Pharmacology and Therapeutics