Brain and cerebrospinal fluid distributions of metoprolol in rats

The distribution of metoprolol tartrate (MPL) into the brain and cerebrospinal fluid (CSF) from plasma was determined at 2 different steady-state plasma concentrations (2 and 20 nmol/ml) and following intravenous bolus administration (100 nmol/kg) in rats. Under steady-state condition, no difference in the brain and CSF distributions of MPL was observed between 2 different plasma MPL concentrations, and the value of brain- or CSF-to-plasma partition coefficients were 5.7 and 1.5, respectively. Following intravenous administration, MPL distributed into CSF very rapidly and its initial uptake phase was not detected. On the other hand, MPL distribution into the brain was relatively slow with the uptake phase. Thus, the brain uptake of MPL from the plasma was pharmacokinetically analyzed using a modified 2-compartment model and deconvolution method, whereas the CSF distribution of MPL was not adequate for kinetic analysis because of the lack of uptake phase. The analysis of brain uptake of MPL by both compartment model and deconvolution gave the same results and the calculated brain Kp value of MPL was almost comparable with that of observed Kp value under steady-state plasma concentration. The distribution of MPL into CSF was considered mainly depending on the pH difference between the plasma and CSF, and the mutual transfer of MPL between CSF and the brain tissue was considered to be negligible from an in vitro study.