Nasal delivery of P-gp substrates to the brain through the nose-brain pathway.

The objective of this study was to evaluate in rats the potential utility of the nasal route to enhance central nervous system (CNS) delivery of drugs recognized by P-glycoprotein (P-gp). Well-known P-gp substrates verapamil and talinolol were perfused nasally or infused intravenously, and when plasma concentrations following intravenous infusion and nasal perfusion showed similar profiles. The concentration of verapamil in the brain after nasal perfusion was twice that after intravenous infusion. Although talinolol in the brain and the cerebrospinal fluid after i.v. infusion were below the detection limit, it was detected after nasal perfusion. When rats were treated with cyclosporin A, brain concentrations of verapamil after both administration modes were increased significantly, while those of talinolol were not significantly changed. Since the permeability of talinolol is low, talinolol in the brain which was transported directly from the nasal cavity has little chance of transport by P-gp localized in the apical membrane of cerebral microvessel endothelial cells. The potential for drug delivery utilizing the nose-CNS route was confirmed for P-gp substrates. The advantage of nasal delivery over i.v. delivery of talinolol to the brain was more significant than that of verapamil, suggesting that nasal administration is more useful strategy for the brain delivery of low-permeability P-gp substrates than the use of P-gp inhibitors.

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.

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.

Side effects of beta-blocker treatments as related to the central nervous system.

During the last decade beta-adrenoceptor antagonists have become one of the first-line treatments for hypertension. Generally, they have been shown to be safe with a low frequency of serious side effects. However, minor subjective symptoms, usually considered to be CNS-related, have been reported for all beta-blockers used. Thus, all beta-blockers on the market seem to have a high benefit:risk ratio; independent of their physicochemical properties and pharmacodynamic profile, however, they seem to cause CNS-related side effects to about the same extent. These minor side effects, the mechanisms of which are unclear, consist of subtle effects on general well being, decreased initiative, a depressed frame of mind, and disturbed sleep. Generally, however, beta-blockers in therapeutic dosages do not affect the qualitative functions of the brain. The results so far available have been obtained primarily by using objective methods. Further comparison has now been initiated using documented subjective methods to investigate whether the objectively documented differences are of any clinical relevance to the patient's quality of life. Although it cannot be claimed with certainty, nonselective beta-blockers seem to cause CNS-related side effects to a greater extent than beta 1-selective blockers. Differences in the degree of hydrophilicity of the beta-blocker are apparently of no clinical relevance in this respect. Rather, the plasma concentration of the beta-blocking drug (degree of beta-blockade) seems to be the major determinant of whether or not CNS-related symptoms appear in susceptible patients.

Distribution of beta-adrenoceptor blocking drugs into cerebrospinal fluid in rats.

The distribution into cerebrospinal fluid (CSF) of five 3H- or 14C-labelled beta-adrenoceptor blocking drugs given intravenously was studied in urethane-anaesthetized rats. The doses (mg/kg) were: alprenolol 5, metoprolol 1, oxprenolol 5, pindolol 0.5, propranolol 0.1 and 5. Within 15 min. a marked fraction of the given radioactivity appeared in CSF with all substances. During the follow-up period of 315 min., only propranolol, independently of dose, caused high CSF/plasma ratios (0.54-0.73) of radioactivity. The other four beta-adrenoceptor blocking drugs caused levels of CSF radioactivity which were 0.05-0.28 of that in plasma and 0.05-0.14 of the calculated levels of activity in the whole body. Since propranolol is bound to plasma proteins to a higher degree than the other drugs studied, the penetration of the unbound fraction of propranolol into rat CSF is even more pronounced than what would be expected on the basis of CSF/plasma ratio measured.

Brain levels and acute antihypertensive activity of beta-blockers.

The penetration of beta-adrenoceptor blockers into the cerebrospinal fluid and into brain tissue is related to the lipophilicity of these drugs, as reflected by the partition coefficients between octanol and aqueous buffers. However, experimental techniques in animal models show no obvious relationships between the degree of brain penetration and the acute central antihypertensive effect of certain beta-blockers. This discrepancy is demonstrated convincingly by comparative experiments with atenolol and metoprolol. Both drugs are beta 1-selective blockers, and atenolol is highly polar, whereas metoprolol is lipophilic. Both these beta-blockers penetrate the CNS but to differing degrees. The experiments performed with these compounds support other studies described in the literature and do not suggest that there is a central mechanism which underlies the antihypertensive activity of beta-blockers.

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-adrenoceptor blockers and the blood-brian barrier.

1 This study on 21 neurosurgical patients was set up to investigate the extent to which four chronically administered beta-adrenoceptor blockers, propranolol, oxprenolol, metoprolol and atenolol, cross and blood-brain barrier and enter the cerebrospinal fluid (CSF) and brain tissue. The concentration in the CSF of the three lipophilic beta-adrenoceptor blockers, propranolol, oxprenolol and metoprolol, approximated to the free drug concentration in the plasma, and was a poor predictor of brain concentration. These three lipophilic beta-adrenoceptor blockers appeared in brain tissue at concentrations 10-20 times greater than that of hydrophilic atenolol. The approximate brain/plasma ratio for propranolol was 26, for oxprenolol 50, for metoprolol 12 and for atenolol 0.2. 2 The low concentration of atenolol in brain tissue is possibly responsible for the low incidence of central nervous system-related side effects in patients on this agent compared to lipophilic beta-adrenoceptor blockers.