Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples.

BACKGROUND: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. METHODS: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. RESULTS: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. CONCLUSION: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.

Enantioselective assay of beta-receptor antagonists present in microdialysis and plasma samples of rats.

The enantiomers of alprenolol, metoprolol, and propranolol have been separated on an enantioselective cellulase column and analysed using a fully automated HPLC system involving coupled column chromatography and fluorescence detection. The assays had sufficient selectivity and sensitivity to investigate the disposition of these beta 2-receptor antagonists in blood and brain extracellular fluid of rats. A cellulase column was used as the first column to separate the enantiomers giving separation factors between 2.9 and 4.3. After the separation, the enantiomers were trapped on two small precolumns by the use of a switching valve and were then introduced on an achiral C18 analytical column by eluting the small columns backward. The enantiomers in blood and brain tissue dialysates were analysed by direct injection of 8 microliters samples. The limit of quantitation was 0.025-0.4 micrograms/ml of the different enantiomers. Plasma samples were analysed after a simple extraction procedure. The intraassay precision of the lowest quality control plasma samples (0.2-0.8 micrograms rac-drug/ml) was 4-8% for the different enantiomers.

Receptor occupancy in lumbar CSF as a measure of the antagonist activity of atenolol, metoprolol and propranolol in the CNS.

1. The antagonist activity of atenolol, metoprolol and propranolol in the CNS was estimated by determining the extent to which the drugs occupy animal beta 1- and beta 2-receptors in CSF ex vivo at the time of lumbar puncture. 2. Five CSF and plasma samples were obtained 4 h after drug intake from subjects treated for hypertension with atenolol, 100 mg once daily and five from subjects treated with metoprolol, 50 mg three times daily. Twenty-four samples were obtained 1, 2, 4 or 12 h after drug intake from subjects receiving a single 40 mg dose of propranolol. 3. The receptor occupancy in the samples was determined by adding beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes into the samples and labeling the receptors with a nonselective beta-adrenoceptor antagonist, (-)-[3H]-CGP-12177. 4. Atenolol and metoprolol occupied, as expected, larger fractions of beta 1- than beta 2-receptors in CSF and plasma samples. The receptor fraction occupied by atenolol in CSF was significantly (P < 0.05) lower than that occupied by metoprolol. The differences in occupancy between the drugs in plasma, however, were not statistically significant. 5. Propranolol occupied larger fractions of beta 2- than beta 1-receptors in the samples. Although propranolol concentrations in CSF were only 1/20-1/40 of those in plasma, the receptor occupancy of propranolol in CSF was similar to that in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Central nervous system kinetics of atenolol and metoprolol in the dog during long term treatment.

Beagle dogs with catheters chronically implanted into the lateral cerebral ventricle were used to study the distribution of atenolol and metoprolol between the cerebrospinal fluid (CSF) and blood plasma over a 24-hr period during long term treatment. The concentration of atenolol declined more slowly in CSF than in blood plasma and the CSF/plasma ratio of atenolol (after iv administration for 7 days) increased from 0.08 +/- 0.02 (2 hr after dose) to 0.83 +/- 0.14 (24 hr after dose) (mean +/- SD). Furthermore, the CSF concentration of atenolol, relative to the plasma concentration, increased during repeated drug administration. The CSF/plasma ratio 24 hr after an iv dose was 0.48 +/- 0.12 on day 1 and 0.83 +/- 0.14 on day 7. The CSF concentration of the more lipophilic beta 1-adrenoceptor antagonist metoprolol was almost the same as the concentration of the drug in blood plasma. After 7 days of oral treatment, the CSF/plasma ratio of metoprolol 24 hr after dosing was 0.81 +/- 0.10. The regional CSF concentration of atenolol along the neuraxis was determined in anaesthetized dogs after acute iv administration of the drug. The atenolol concentration in CSF from the lateral cerebral ventricle was similar to that in the cisterna magna but lower than the concentration in CSF sampled from the lumbar region. It is concluded that the CSF concentration of the moderately lipophilic beta 1-adrenoceptor antagonist metoprolol equilibrates with the plasma concentration of the drug more rapidly compared with the hydrophilic drug atenolol.

High-performance liquid chromatographic determination of metoprolol and alpha-hydroxymetoprolol concentrations in human serum, urine, and cerebrospinal fluid.

A sensitive and simplified high-performance liquid chromatographic procedure was developed for the simultaneous quantification of metoprolol and alpha-hydroxymetoprolol in human serum, as well as cerebrospinal fluid and urine. Following protein precipitation with trichloroacetic acid, the sample was alkalinized with 1 M NaOH and extracted with dichloromethane. The mobile phase consisted of acetonitrile-water (50:50) containing 0.005 M 1-heptanesulfonic acid in 0.001% acetic acid. Using pronetalol as an internal standard, compounds were quantitated using fluorescence detection at 230 nm with a 300-nm emission filter and 0.02 AUFS. Extraction recovery is approximately 80% for both compounds. The lower limits of detection are 5 ng/mL and 4 ng/mL for metoprolol and alpha-hydroxymetoprolol, respectively.

beta-Adrenoreceptor-blocking agents and the blood-brain barrier.

1. Sixteen neurosurgical patients received (oral) beta-adrenoreceptor-blocking agents (beta-receptor blockers) for 3-22 days. 2. Lipophilic beta-receptor blockers (propranolol) and metoprolol appeared in cerebrospinal fluid at concentrations similar to the free drug plasma concentration. 3. Cerebrospinal fluid concentrations of beta-receptor blockers were poor predictors of brain concentrations. 4. Both lipophilic beta-receptor blockers appeared in high concentrations in the brain: the brain/plasma ratio was approximately 15:1. 5. Hydrophilic atenolol appeared at low concentrations in brain tissue (about 20 times lower than the lipophilic beta-receptor blockers): the brain/plasma ratio was approximately 0.1:1. 6. Central nervous system-related side effects associated mainly with lipophilic beta-receptor blockers possibly result from high brain tissue concentrations.

Comparison between the acute hemodynamic effects and brain penetration of atenolol and metoprolol.

Atenolol and metoprolol are beta 1-selective adrenergic receptor blockers, devoid of local anesthetic and intrinsic sympathomimetic properties. Their antihypertensive and hypotensive activities are equivalent. They differ with respect to their lipophilic character, as is apparent from their octanol/buffer (pH, 7.4 at 37 degrees C) partition coefficients: metoprolol, 1.084; atenolol, 0.012. We compared the two agents with regard to their acute hemodynamic effects and degree of penetration into the cerebrospinal fluid (CSF) and into the brain. For this purpose [3H]-metoprolol and [14C]-atenolol were injected either intravenously or into the left vertebral artery of chloralose-anesthetized cats. With both routes of administration, metoprolol, the more lipophilic of the two compounds, achieved much higher concentrations in the CSF and in the pontomedullary region than did atenolol. One hour after completion of an intravenous injection, the concentration of metoprolol in the CSF was about 6.5 times higher than that of atenolol; after administration into the vertebral artery, the difference was about ninefold. In spite of these considerable differences, the hypotensive and bradycardic activities of both drugs, administered intravenously or into the left vertebral artery, were virtually the same. These results suggest that the acute hemodynamic effects of metoprolol and atenolol are probably not due to an action within the central nervous system, but rather to a peripheral mechanism.