The Effect of Dosage Release Formulations on the Pharmacokinetics of Propranolol Stereoisomers in Humans

Recent studies in dogs have suggested that the disposition of S‐ and R‐propranolol may depend on the input rate of drug delivered to the liver. Therefore, this study was designed to determine whether differences in the disposition of S‐ and R‐propranolol occur in humans when altering the input rate of propranolol by giving different dosage forms of the drug. Twelve healthy subjects were enrolled in a single‐dose, 4‐way crossover pharmacokinetic study in which racemic propranolol was given according to 1 of 4 treatments: one 80‐mg immediate‐release (IR) tablet, phase A; two 80‐mg IR tablets, phase B; a 160‐mg controlled‐release capsule, phase C; or a 10‐mg IV bolus, phase D. The results showed no significant differences in the ratios of S/R‐propranolol for AUC, clearance, or overall mean concentration among the oral dosage groups. Significant differences in these parameters including C_max S/R ratio were seen between the oral phases and the IV phase. These differences appear to be related more to the route of administration than to the low input rate. However, at high concentrations there may be input‐rate alteration in S/R ratios. Specifically, for phase B, which had the highest C_max concentrations, the C_max S/R ratio was significantly lower than the other oral dosage groups A and C (C_max S/R ratios: 1.44 versus 1.54 and 1.54, respectively; P < .05). These results suggest, as shown by the C_max S/R ratio, that at high concentrations as seen after 160‐mg IR propranolol, the disposition of S‐ and R‐enantiomers may be different (i.e., input‐rate dependent) compared with dosage forms that result in lower drug concentrations. This may have important clinical implications, because the pharmacodynamic response may be altered. 1995 American College of Clinical Pharmacology