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 liv er. Therefore, this study was designed to determine whether difference s in the disposition of S- and R-propranolol occur in humans when alte ring the input rate of propranolol by giving different dosage forms of the drug. Twelve healthy subjects were enrolled in a single-dose, 4-w ay crossover pharmacokinetic study in which racemic propranolol was gi ven according to 1 of 4 treatments: one 80-mg immediate-release (IR) t ablet, phase A; two 80-mg IR tablets, phase B; a 160-mg controlled-rel ease capsule, phase C; or a 10-mg IV bolus, phase D, The results showe d no significant differences in the ratios of S/R-propranolol for AUG, clearance, or overall mean concentration among the oral dosage groups . Significant differences in these parameters including C-max S/R rati o were seen between the oral phases and the IV phase, These difference s appear to be related more to the route of administration than to the low input rate. However, at high concentrations there may be input-ra te alteration in S/R ratios. Specifically, for phase B, which had the highest C-max concentrations, the C-max S/R ratio was significantly lo wer 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, a s shown by the C-max S/R ratio, that al high concentrations as seen af ter 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 clin ical implications, because the pharmacodynamic response may be altered .