Pharmacokinetics, central nervous system uptake, and lipid solubility of propranolol, acebutolol, and sotalol

The relation of in vitro lipophilicity, based on octanol:buffer partition ratio and on reverse-phase liquid chromatographic retention, to in vivo pharmacokinetics and central nervous system entry was evaluated for the beta-blockers propranolol, acebutolol, and sotalol. Anesthetized cats received single intravenous doses, following which plasma kinetics, cerebrospinal fluid (CSF) kinetics and brain tissue uptake were determined over the next 4 h. Propranolol, by far the most lipophilic beta-blocker in vitro, had the highest in vivo metabolic clearance and volume of distribution (V(d)), the most rapid entry into CSF, and the highest brain:plasma uptake ratio (38.0). Sotalol, the most hydrophilic drug in vitro, had the lowest in vitro clearance and V(d), the slowest CSF entry, and the lowest brain:plasma ratio (0.52). Acebutolol had slightly greater in vitro lipophilicity than sotalol, intermediate values of in vivo plasma kinetics and CSF entry rate, and a slightly greater brain:plasma uptake ratio (0.71). Thus, differences among beta-blockers in lipid solubility are associated with predictable differences in plasma kinetics, and rate of entry into CSF. Furthermore, the relative extent of entry into brain is lower for hydrophilic as opposed to lipophilic beta-blockers.