[Mechanisms of nutrient and drug transfer through the blood-brain barrier and their pharmacological changes]. / Mécanismes de transfert à travers la barrière hémato-encéphalique des nutriments et des médicaments et leurs modifications pharmacologiques.

The blood-brain barrier is formed by the endothelial cells of the brain capillaries. Its primary characteristic is the impermeability of the capillary wall due to the presence of complex tight junctions and a low endocytic activity. Essential nutrients are delivered to the brain by selective transport mechanisms, such as glucose transporter and a variety of amino acid transporters. Although most drugs enter the brain by passive diffusion through the endothelial cells depending of their lipophilicity, degree of ionization, molecular weight, relative brain tissue and plasma bindings--some of them can use specific endogenous transporters. In these cases, binding competition on the transporter with endogenous products or nutrients can occur and limit the drug transfer. The blood-brain barrier can be a major impediment for the treatment of diseases of the central nervous system, since many drugs are unable to reach this organ at therapeutic concentrations. Various attempts have been made to overcome the limiting access of drugs to the brain: chemical modification of drugs, development of more hydrophobic analogs or linking an active compound to a specific carrier. Transient opening of the blood-brain barrier has been achieved by intracarotid infusion of hypertonic mannitol solutions or of bradykinin analogs in humans. Another way to increase or decrease brain delivery of drugs is to modulate the P-glycoprotein (P-gp) whose substrates are actively pumped out the cell into the capillary lumen. We actually dispose of many P-gp inhibitors or inducers in order to enhance the therapeutic effects of centrally acting drugs or to decrease central adverse effects of peripheric drugs.

Drug transfer across the blood-brain barrier and improvement of brain delivery.

The blood-brain barrier is formed by the endothelial cells of the brain capillaries. Its primary characteristic is the impermeability of the capillary wall due to the presence of complex tight junctions and a low endocytic activity. Essential nutrients are delivered to the brain by selective transport mechanisms, such as the glucose transporter and a variety of amino acid transporters. Although most drugs enter the brain by passive diffusion through the endothelial cells depending on their lipophilicity, degree of ionization, molecular weight, relative brain tissue and plasma bindings, some others can use specific endogenous transporters. In such cases, binding competition on the transporter with endogenous products or nutrients can occur and limits drug transfer. The blood-brain barrier can be a major impediment for the treatment of diseases of the central nervous system, since many drugs are unable to reach this organ at therapeutic concentrations. Various attempts have been made to overcome the limiting access of drugs to the brain, e.g. chemical modification, development of more hydrophobic analogs or linking an active compound to a specific carrier. Transient opening of the blood-brain barrier in humans has been achieved by intracarotid infusion of hypertonic mannitol solutions or of bradykinin analogs. Another way to increase or decrease brain delivery of drugs is to modulate the P-glycoprotein (P-gp) whose substrates are actively pumped out the cell into the capillary lumen. Many P-gp inhibitors or inducers are available to enhance the therapeutic effects of centrally acting drugs or to decrease central adverse effects of peripherally active drugs.

The genetic variant A of human alpha 1-acid glycoprotein limits the blood to brain transfer of drugs it binds.

The objective of this work was to check the effects of alpha-1 acid glycoprotein (AAG) and of its components, A and F1/S genetic variants, on the brain transfer of drugs they bind in plasma. The relevant extractions of six basic drugs, highly bound to AAG, were measured. We chose three drugs selectively bound to the A variant, disopyramide, imipramine and methadone, one drug mainly bound to the mixture F1/S, mifepristone, and two drugs which were simultaneously bound to the variant A and the mixture F1/S, propranolol and chlorpromazine. Their brain extraction were investigated in rats using the carotid injection technique and the capillary depletion method. Injected drugs were dissolved either in buffer, either in native AAG containing the three variants (A, F1 and S), either in variant A or in variant F1/S solutions. Brain extractions of disopyramide, imipramine and methadone were significantly reduced by native AAG and by variant A. Drug's plasma retention was related to their preferential and almost exclusive binding to A variant, both of them exhibiting the same decrease in brain transfer as compared to a buffered solution. At the opposite, there were no significative differences between the extraction either in buffer, either in AAG or in F1/S solutions, of drugs both bound to A variant and F1/S mixture (chlorpromazine and propranolol) or to the F1/S mixture (mifepristone). In serum, the retentional effect of the A variant on the extraction of disopyramide and imipramine was counteracted by the presence of albumin and lipoproteins, which simultaneously bind these two drugs at a high extent and act as permissive binders. We conclude that AAG binding decreases brain drug transfer when the A variant is mainly and almost exclusively involved in the binding. On the contrary, the entire fraction of the tested drugs when bound exclusively or partly to the mixture F1/S is available for transfer into the brain.

Plasma assay of salbutamol by means of high-performance liquid chromatography with amperometric determination using a loop column for injection of plasma extracts. Application to the evaluation of subcutaneous administration of salbutamol.

An isocratic high-performance liquid chromatography method with amperometric detection for the assay of plasma salbutamol is described. The plasma extract is injected into the chromatographic system via a loop column. This insures the purification of the injected extracts and allows a simple and rapid liquid-solid extraction procedure. The good reliability, as shown by the low limit of detection (0.5 ng/ml) and a precision ranging between 5 and 10%, has permitted the investigation of a new mode of administration of salbutamol using a portable subcutaneous infusion pump. Our results show that subcutaneous administration yields plasma levels comparable with those obtained after usual intravenous doses.

Drug transfer across the blood-brain barrier: correlation between in vitro and in vivo models.

To assess the drug transport across the blood-brain barrier (BBB), we compared the maximal brain extraction values at time 0 [E(0) values] obtained using either in vitro or in vivo methods. The in vitro BBB model consisted of a coculture of brain capillary endothelial cells growing on one side of a filter and astrocytes on the other. The in vivo model used intracarotid injection in anesthetized rats. Eleven compounds were tested. They were selected because they exhibit quantitatively different brain extraction rates: very low for inulin and sucrose, low for oxicam-related nonsteroidal antiinflammatory drugs and diclofenac, and high for propranolol and diazepam. As these compounds are apparently transferred by a passive diffusion mechanism, two others, glucose and leucine, were added that cross the BBB by a known carrier-mediated process. The in vivo and in vitro E(0) values showed a strong correlation as indicated by the Spearman's correlation coefficient (r = 0.88, p less than 0.01). The relative ease with which such cocultures can be produced in large quantities could facilitate the screening of new centrally acting drugs.