Application of intracerebral microdialysis to study regional distribution kinetics of drugs in rat brain.

1. The purpose of the present study was to determine whether intracerebral microdialysis can be used for the assessment of local differences in drug concentrations within the brain. 2. Two transversal microdialysis probes were implanted in parallel into the frontal cortex of male Wistar rats, and used as a local infusion and detection device respectively. Within one rat, three different concentrations of atenolol or acetaminophen were infused in randomized order. By means of the detection probe, concentration-time profiles of the drug in the brain were measured at interprobe distances between 1 and 2 mm. 3. Drug concentrations were found to be dependent on the drug as well as on the interprobe distance. It was found that the outflow concentration from the detection probe decreased with increasing lateral spacing between the probes and this decay was much steeper for acetaminophen than for atenolol. A model was developed which allows estimation of kbp/Deff (transfer coefficient from brain to blood/effective diffusion coefficient in brain extracellular fluid), which was considerably larger for the more lipohilic drug, acetaminophen. In addition, in vivo recovery values for both drugs were determined. 4. The results show that intracerebral microdialysis is able to detect local differences in drug concentrations following infusion into the brain. Furthermore, the potential use of intracerebral microdialysis to obtain pharmacokinetic parameters of drug distribution in brain by means of monitoring local concentrations of drugs in time is demonstrated.

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)

Nonlinear distribution of atenolol between plasma and cerebrospinal fluid.

Long Evans rats were given atenolol doses ranging from 0.27 to 5.4 mg/kg by intraperitoneal injection Animals were dosed once every 2 hr for a total of five doses. Atenolol concentrations 1 hr after the last dose were measured from simultaneously obtained plasma and cerebrospinal fluid (CSF) samples CSF concentrations of atenolol were not proportional to plasma concentrations. The ratio of CSF/plasma concentrations was higher (0.33) at lower plasma atenolol levels (less than 100 ng/ml) than at the higher atenolol plasma levels (0.05) (P less than 0.001). The relationship between plasma and cerebrospinal fluid atenolol concentrations was best described by the sum of a Michaelis-Menten and linear function. Animals were also given atenolol doses and then subjected to global cerebral ischemia. The relationship of atenolol concentrations from plasma and CSF in these animals was linear, with a constant partition ratio of 0.02. Together these data show that atenolol partitioning between plasma and CSF is nonlinear and possibly an energy-dependent process.

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.

Cerebrospinal fluid concentrations of propranolol, pindolol and atenolol in man: evidence for central actions of beta-adrenoceptor antagonists.

1 Single and multiple oral dose studies of the penetration into CSF of three beta-adrenoceptor antagonists were performed in groups of patients needing lumbar puncture as part of their neurological investigation. Propranolol, pindolol and atenolol were chosen because of their differing physico-chemical properties. 2 The CSF concentration of propranolol (lipid-soluble) and pindolol (moderately lipid-soluble) was proportional to the free plasma concentration and was similar to, although generally lower than, that theoretically predicted. 3 The CSF concentrations of the poorly lipid-soluble atenolol were similar in different patients and were independent of plasma concentration. This may be due to the slow rate of diffusion of atenolol into CSF preventing the predicted concentrations being achieved.

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.