Biomedical subjects

A G de Boer

Publications and source records attributed to A G de Boer.

At least 19 recordsLinked to original sources

PubMed2007

Drug targeting to the brain.

The central nervous system (CNS) is a sanctuary site and is protected by various barriers. These regulate brain homeostasis and the transport of endogenous and exogenous compounds by controlling their selective and specific uptake, efflux, and metabolism in the brain. Unfortunately, potential drugs for the treatment of most brain diseases are therefore often not able to cross these barriers. As a result, various drug delivery and targeting strategies are currently being developed to enhance the transport and distribution of drugs into the brain. Here we discuss briefly the biology and physiology of the blood-brain barrier (BBB) and the blood-cerebro-spinal-fluid barrier (BCSFB), and, in more detail, the possibilities for delivering large-molecular-weight drugs by local and global delivery and by viral and receptor-mediated nonviral drug delivery to the (human) brain.

Biological Transport↗

PubMed2006

Blood-brain barrier dysfunction and recovery.

In this paper we discuss the importance of the blood-brain barrier (BBB) as an interface between blood and brain. Many (brain) diseases change the functionality and integrity of the BBB. Mostly this results in increased BBB permeability. Therefore we have studied de various signal transduction routes that are influenced by inflammatory stimuli. The radical scavenger N-acetylcysteine was able to protect the BBB against inflammatory stimuli. Similar results were found following application of glucocorticoids. In addition, it was observed that glucocorticoids and interferon-alpha,beta increased the tightness of the in vitro BBB and when given together a potentiating effect was seen.

Animals↗

PubMed2005

Patient satisfaction with occupational health physicians, development of a questionnaire.

AIMS: To develop a questionnaire that measures specific aspects of patient satisfaction with occupational health physicians. METHODS: General patient satisfaction questionnaires, a literature survey, and interviews with patients were used. An initial questionnaire was distributed among sick listed patients (n = 432) of occupational physicians (n = 90) from different occupational health services. To reduce items and to develop scales exploratory factor analysis and reliability analysis was used. A linear regression model was used to predict satisfaction ratings from the scales of the questionnaire. RESULTS: Questions about independence of the occupational physician were difficult to ask unambiguously. The factor analysis revealed five relevant factors which were named "being taken seriously as a patient", "attitude towards occupational health services", "trust and confidentiality", "expectations", and "comfort and access". All scales could be reduced to a maximum of five items without reducing the scale reliability too much. In the regression analysis, 71% of the variance of satisfaction ratings was explained by the first four scales and most by the first scale. "Comfort and access" did not contribute significantly to the model. CONCLUSIONS: A short questionnaire was developed to measure different aspects of patient satisfaction specific for occupational health. Whether the questionnaire can effectively lead to quality improvement in occupational health services should be investigated.

Adult↗

PubMed2002

The role of drug transporters at the blood-brain barrier.

The blood-brain barrier (BBB) is a dynamic interface between the blood and the brain. It eliminates (toxic) substances from the endothelial compartment and supplies the brain with nutrients and other (endogenous) compounds. It can be considered as an organ protecting the brain and regulating its homeostasis. Until now, many transport systems have been discovered that play an important role in maintaining BBB integrity and brain homeostasis. In this review, we focus on the role of carrier- and receptor-mediated transport systems (CMT, RMT) at the BBB. These include CMT systems, such as P-glycoprotein, multidrug-resistance proteins 1-7, nucleoside transporters, organic anion transporters, and large amino-acid transporters; RMT systems, such as the transferrin-1 and -2 receptors; and the scavenger receptors SB-AI and SB-BI.

Biological Transport, Active↗

PubMed2002

High prevalence of the neurotrope Exophiala dermatitidis and related oligotrophic black yeasts in sauna facilities.

The black yeast Exophiala dermatitidis, an agent of fatal brain infections in East Asia, is common in European steam baths. The related fungi Sarcinomyces phaeomuriformis and Exophiala mesophila were isolated from locations in these complexes with lower ambient temperature and/or moisture. The latter two species had dry, rather than slimy, colonies and lower maximum growth temperatures (38 degrees C, 32 degrees C) than E. dermatitidis (42 degrees C). Exophiala dermatitidis produces abundant extracellular polysaccharide (EPS). The only E. dermatitidis strains lacking EPS were found outside the steam baths. Therefore it is likely that the extracellular polysaccharides commonly produced by E. dermatitidis are significant to survival under hot and moist conditions. Substrates sampled as controls, such as fruit surfaces and human faeces, yielded Exophiala dermatitidis at very low frequency.

Baths↗

PubMed2001

Glucocorticoid and type 1 interferon interactions at the blood-brain barrier: relevance for drug therapies for multiple sclerosis.

The pharmacological effect of glucocorticoids and type 1 interferons (IFNs), simultaneously used as therapeuticals for multiple sclerosis (MS), on the (inflamed) blood-brain barrier (BBB) was investigated in vitro. Although both drugs additively decreased BBB permeability, they did not prevent the increase in BBB permeability induced by lipopolysaccharide (LPS), which served as a pro-inflammatory stimulus. The beneficial clinical effect of glucocorticoid and IFN therapy for MS seems there- fore not to be mediated through a direct action at the level of the BBB. Most strikingly, however, pretreatment with type 1 IFNs (alpha and beta) potentiated the effect of glucocorticoids by two orders of magnitude. This lead us to hypothesize that type 1 IFNs may restore the dysfunctional T-helper 1 (Th1)/Th2 balance associated with MS, by a mechanism that involves an increased sensitivity for glucocorticoids.

Animals↗

PubMed2001

Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood--brain barrier.

OBJECTIVE: To investigate the involvement of P-glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP) on the active transport of the HIV protease inhibitors amprenavir, ritonavir and indinavir. METHODS: The transport behaviour of ritonavir, indinavir and amprenavir in the presence and absence of Pgp modulators and probenecid was investigated in an in vitro blood--brain barrier (BBB) co-culture model and in monolayers of LLC-PK1, LLC-PK1:MDR1, LLC-PK1:MRP1 and Caco-2 cells. RESULTS: All three HIV protease inhibitors showed polarized transport in the BBB model, LLC-PK1:MDR1 and Caco-2 cell line. The Pgp modulators SDZ-PSC 833, verapamil and LY 335979 inhibited polarized transport, although their potency was dependent on both the cell model and the HIV protease inhibitor used. Ritonavir and indinavir also showed polarized transport in the LLC-PK1 and LLC-PK1:MRP1 cell line, which could be inhibited by probenecid. HIV protease inhibitors were not able to inhibit competitively polarized transport of other HIV protease inhibitors in the LLC-PK1:MDR1 cell line. CONCLUSIONS: Amprenavir, ritonavir and indinavir are mainly actively transported by Pgp, while MRP also plays a role in the transport of ritonavir and indinavir. This indicates that inhibition of Pgp could be useful therapeutically to increase HIV protease inhibitor concentrations in the brain and in other tissues and cells expressing Pgp. The HIV protease inhibitors were not able to inhibit Pgp-mediated efflux when given simultaneously, suggesting that simultaneous administration of these drugs will not increase the concentration of antiretroviral drugs in the brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Establishment and functional characterization of an in vitro model of the blood-brain barrier, comprising a co-culture of brain capillary endothelial cells and astrocytes.

OBJECTIVE: The aim was to establish a flexible, abundantly available, reproducible and functionally characterized in vitro model of the blood-brain barrier (BBB). METHODS: In a first step, bovine brain capillaries and newborn rat astrocytes were isolated. Subsequently, a co-culture of primary brain capillary endothelial cells (BCEC) on semi-permeable filter inserts, with astrocytes on the bottom of the filter was established. The cell material was characterized on the basis of specific cell-type properties and (functional expression of) specific BBB properties. RESULTS: BCEC displayed: (1) characteristic endothelial cell morphology; (2) expression of endothelial cell markers (i.e., CD51, CD62P, CD71 and cadherin 5); (3) marginal F-actin localization; (4) tight junction formation between the cells; (5) expression of gamma-glutamyl-transpeptidase (gamma-GTP); (6) expression of P-glycoprotein (Pgp); (7) functional transendothelial transferrin transport and uptake; (8) restriction of paracellular transport; and (9) high transendothelial electrical resistance (TEER). Astrocytes displayed characteristic astrocyte morphology and expressed glial fibrillary acidic protein (GFAP). Co-culture with astrocytes increased TEER and decreased paracellular transport. In addition, expression of the glucocorticoid receptor (GR) was demonstrated in the endothelial cells of the BBB, while no expression of the mineralocorticoid receptor (MR) was found. CONCLUSIONS: A high quality and mass-production in vitro BBB model was established in which experiments with physiological (e.g., regulation of BBB permeability), pharmacological (e.g., pharmacokinetics and pharmacodynamics) and pathophysiological (e.g., disease influence on BBB permeability) objectives can be reproducibly performed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Active efflux of the 5-HT(1A) receptor agonist flesinoxan via P-glycoprotein at the blood-brain barrier.

The role of P-glycoprotein on the efflux of the 5-HT(1A) receptor agonist flesinoxan across the blood-brain barrier in vivo and in vitro was investigated. In vitro, the transport ratios (representing polarized transport) of flesinoxan (10 microg/ml) were 4.2 in the MDR1-transfected LLC-PK1 cell line, which could be inhibited by the Pgp modulators SDZ-PSC 833 and LY 335979 and 1.1 in the wild-type LLC-PK1 cell line after 4 h. Flesinoxan concentrations lower than 33 microg/ml were actively transported by Pgp, while at higher concentrations Pgp became saturated and transport in the MDR1-transfected cell line was comparable with the wild-type cell line. In the in vitro BBB co-culture model the transport ratio was 2.0 and was decreased to 1.0 in the presence of Pgp modulators. In vivo, the accumulation of flesinoxan in the brain at 3 h was much higher in the mdr1a(-/-) mice compared to mdr1a(+/+) mice (ratio 12.6 and 27.0 at dose levels of 3 mg/kg and 10 mg/kg respectively). In conclusion, both in vivo as well as in vitro results have demonstrated that Pgp is a limiting factor for the transport of the 5-HT(1A) receptor agonist flesinoxan into the CNS. This should be considered when its application in therapy is combined with other Pgp substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

A fallacy of the multiplicative QALY model for low-quality weights in students and patients judging hypothetical health states.

OBJECTIVES: In quality-adjusted life-years (QALY) models, it is customary to weigh life-years with quality of life via multiplication. As a consequence, for positive health states a longer duration has more QALYs than a shorter duration (i.e., longer is better). However, we have found that for poor health states, many prefer to live only a limited amount of time (i.e., longer is worse). Such preferences are said to be maximum endurable time (MET). In the present contribution, the following questions are asked: a) How low does the utility have to be in order for a MET to arise? and b) Do MET preferences occur when patients judge hypothetical health states? METHODS AND RESULTS: We reanalyzed data from 176 students for the hypothetical health states of "living with migraines" and "living with metastasized cancer." For utilities smaller than 0.7 (ranging from 0 to 1), the MET preference rate was larger than 50%. High MET preference rates were also found in two new studies on migraine and esophageal cancer patients, who evaluated hypothetical health states related to their disease. CONCLUSIONS: We discuss the interpretation of the MET preferences and the preference reversal phenomenon. Standard QALY models imply that longer is better. However, we find that more often, longer is worse for poorly evaluated health states. Consider the following question: are 3 years with a weight of 0.3 equally as valuable as 1 year with a weight of 0.9? Our results suggest that the 3-year period may be less valuable because for poor health, many will prefer a 1-year over a 3-year period.

Adult↗

PubMed2001

P-glycoprotein inhibition leads to enhanced disruptive effects by anti-microtubule cytostatics at the in vitro blood-brain barrier.

PURPOSE: To investigate whether P-glycoprotein (Pgp) protects the in vitro BBB against the cytotoxic effects of anti-tumour drugs. METHODS: In an in vitro BBB coculture model the influence of the anti-microtubule drugs vinblastine, colchicine, paclitaxel and the non-anti-microtubule drugs doxorubicin, fluorouracil and etoposide in the absence or presence of Pgp modulators on the trans-endothelial electrical resistance (TEER), which is an indicator for the integrity, was investigated. RESULTS: In the absence of Pgp modulators vinblastine, colchicine and paclitaxel dose dependently decreased TEER values to less than 20% of control. Non-anti-microtubule drugs did not affect TEER values. Following competitive inhibition of Pgp by various Pgp modulators and substrates, even low concentrations of vinblastine, colchicine and paclitaxel substantially decreased TEER. IC50 values of LY 335979, SDZ-PSC 833, cyclosporin A, and verapamil were 0.03, 0.25, 0.46, and 13.7 microM, respectively. CONCLUSIONS: These results indicate that Pgp normally protects the in vitro BBB against the disruptive effects of anti-microtubule drugs, but its integrity is lost when anti-microtubule drugs are used in combination with potent Pgp modulators. In addition, this procedure offers the possibility to characterize Pgp modulators and substrates with respect to their efficacy and to elucidate drug interactions at the level of Pgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Evidence of P-glycoprotein mediated apical to basolateral transport of flunisolide in human broncho-tracheal epithelial cells (Calu-3).

1. Transepithelial transport of flunisolide was studied in reconstituted cell monolayers of Calu-3, LLC-PK1 and the MDR1-P-glycoprotein transfected LLC-MDR1 cells. 2. Flunisolide transport was polarized in the apical (ap) to basolateral (bl) direction in Calu-3 cells and was demonstrated to be ATP-dependent. In LLC-MDR1 cells, flunisolide was transported in the bl to ap direction and showed no polarization in LLC-PK1 cells. 3. Non-specific inhibition of cellular metabolism at low temperature (4 degrees C) or by 2-deoxy-D-glucose (2-d-glu) and sodium azide (NaN(3)) abolished the polarized transport. Polarized flunisolide transport was also inhibited by the specific Pgp inhibitors verapamil, SDZ PSC 833 and LY335979. 4. Under all experimental conditions and in the presence of all used inhibitors, no decrease in the TransEpithelial Electrical Resistance (TEER) values was detected. From all inhibitors used, only the general metabolism inhibitors 2-deoxy-D-glucose and NaN(3), decreased the survival of Calu-3 cells. 5. Western blotting analysis and confocal laser scanning microscopy demonstrated the presence of MDR1-Pgp at mainly the basolateral side of the plasma membrane in Calu-3 cells and at the apical side in LLC-MDR1 cells. Mass spectroscopy studies demonstrated that flunisolide is transported unmetabolized across Calu-3 cells. 6. In conclusion, these results show that the active ap to bl transport of flunisolide across Calu-3 cells is facilitated by MDR1-Pgp located in the basolateral plasma membrane.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain.

In the present study, we investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in the control of access of cortisol and corticosterone to the mouse and human brain. [(3)H]Cortisol poorly penetrated the brain of adrenalectomized wild-type mice, but the uptake was 3.5-fold enhanced after disruption of Pgp expression in mdr 1a(-/-) mice. In sharp contrast, treatment with [(3)H]corticosterone revealed high labeling of brain tissue without difference between both genotypes. Interestingly, human MDR1 Pgp also differentially transported cortisol and corticosterone. LLC-PK1 monolayers stably transfected with MDR1 complementary DNA showed polar transport of [(3)H]cortisol that could be blocked by a specific Pgp blocker, whereas [(3)H]corticosterone transport did not differ between transfected and host cells. Determination of the concentration of both steroids in extracts of human postmortem brain tissue using liquid chromatography mass spectrometry revealed that the ratio of corticosterone over cortisol in the brain was significantly increased relative to plasma. In conclusion, the data demonstrate that in both mouse and human brain the penetration of cortisol is less than that of corticosterone. This finding suggests a more prominent role for corticosterone in control of human brain function than hitherto recognized.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Methodological issues in microdialysis sampling for pharmacokinetic studies.

Microdialysis is an in vivo technique that permits monitoring of local concentrations of drugs and metabolites at specific sites in the body. Microdialysis has several characteristics, which makes it an attractive tool for pharmacokinetic research. About a decade ago the microdialysis technique entered the field of pharmacokinetic research, in the brain, and later also in peripheral tissues and blood. Within this period much has been learned on the proper use of this technique. Today, it has outgrown its child diseases and its potentials and limitations have become more or less well defined. As microdialysis is a delicate technique for which experimental factors appear to be critical with respect to the validity of the experimental outcomes, several factors should be considered. These include the probe; the perfusion solution; post-surgery interval in relation to surgical trauma, tissue integrity and repeated experiments; the analysis of microdialysate samples; and the quantification of microdialysate data. Provided that experimental conditions are optimized to give valid and quantitative results, microdialysis can provide numerous data points from a relatively small number of individual animals to determine detailed pharmacokinetic information. An example of one of the added values of this technique compared with other in vivo pharmacokinetic techniques, is that microdialysis reflects free concentrations in tissues and plasma. This gives the opportunity to assess information on drug transport equilibration across membranes such as the blood-brain barrier, which already has provided new insights. With the progress of analytical methodology, especially with respect to low volume/low concentration measurements and simultaneous measurement of multiple compounds, the applications and importance of the microdialysis technique in pharmacokinetic research will continue to increase.

Animals↗

PubMed2000

Effect of degree of quaternization of N-trimethyl chitosan chloride for enhanced transport of hydrophilic compounds across intestinal caco-2 cell monolayers.

N-Trimethyl chitosan chloride (TMC) is a permanently quaternized chitosan derivative with improved aqueous solubility compared to native chitosan. TMC is able to open the tight junctions of intestinal epithelia at physiological pH values, where chitosan is insoluble and therefore ineffective. TMCs with degrees of substitution of 40 and 60% were synthesized according to a novel synthesis procedure and their effect on the permeability of the tight junctions of the intestinal Caco-2 monolayers was studied, measuring the transepithelial electrical resistance and the transport of a mainly paracellularly transported compound, [14C]-mannitol. Toxicity studies using nucleic stains were done to establish the transport as a cause of opening of the tight junctions and not of possible cytotoxicity. TMC60 showed higher transport enhancement ratios than TMC40 in all concentrations tested (0.05-1. 0%, w/v). Both derivatives did not affect the viability of the Caco-2 cell monolayers. These results suggest that high charge density is necessary for TMC to substantially improve the paracellular permeability of intestinal epithelia. It is expected that TMC40 and TMC60 will enhance the intestinal permeation of hydrophilic macromolecular drugs such as peptides and proteins.

Biocompatible Materials↗

PubMed2000

Specificity of doxorubicin versus rhodamine-123 in assessing P-glycoprotein functionality in the LLC-PK1, LLC-PK1:MDR1 and Caco-2 cell lines.

The LLC-PK1:MDR1, LLC-PK1 and Caco-2 cell lines were used to investigate whether rhodamine-123 or doxorubicin would be the preferred substrate to study P-glycoprotein (P-gp) functionality in vitro. Both rhodamine-123 and doxorubicin showed highly polarised transport in the Caco-2 cell line and the LLC-PK1:MDR1 cell line, indicating that P-gp is actively transporting these drugs. However, for rhodamine-123 polarised transport was also seen in the monolayers of the wild-type LLC-PK1 cell line, indicating the presence of another active transporter for this compound. Polarised transport of doxorubicin in the Caco-2 and the LLC-PK1:MDR1 cell lines could be inhibited by the P-gp inhibitors SDZ-PSC 833 (PSC 833), cyclosporin A (CsA), verapamil and quinine, but not by the inhibitors for the organic cation carrier systems cimetidine and tetraethylammonium (TEA). Polarised transport of rhodamine-123 in the Caco-2 cell line could only be inhibited by P-gp inhibitors. In the LLC-PK1:MDR1 and LLC-PK1 cell lines transport was also inhibited by inhibitors for the organic cation transport systems. In conclusion, rhodamine-123 is a substrate for both P-gp and the organic cation carrier systems in the kidney cell line. This indicates that rhodamine-123 is not selective enough to study P-gp functionality in cell systems were organic cation carrier systems are also present. Doxorubicin appears to be a more selective P-gp substrate and therefore more useful in studying P-gp functionality in vitro.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin.

The role of mdr1a-encoded P-glycoprotein on transport of several fluoroquinolones across the blood-brain barrier was investigated. In vitro, P-glycoprotein substrates were selected by using a confluent monolayer of MDR1-LLC-PK1 cells. The inhibition of fluoroquinolones (100 microM) on transport of rhodamine-123 (1 microM) was compared with P-glycoprotein inhibitors verapamil (20 microM) and SDZ PSC 833 (2 microM). Subsequently, transport polarity of fluoroquinolones was studied. Sparfloxacin showed the strongest inhibition (26%) and a large polarity in transport, by P-glycoprotein activity. In vivo, using mdr1a (-/-) and wild-type mice, brain distribution of pefloxacin, norfloxacin, ciprofloxacin, fleroxacin and sparfloxacin was determined at 2, 4, and 6 h following intra-arterial infusion (50 nmol/min). Brain distribution of sparfloxacin was clearly higher in mdr1a (-/-) mice compared with wild-type mice. Sparfloxacin was infused (50 nmol/min) for 1, 2, 3 and 4 h in which intracerebral microdialysis was performed. At 4 h, in vivo recovery (dynamic-no-net-flux method) was 6.5+/-2.2 and 1.5+/-0.5%; brain(ECF) concentrations were 5.1+/-0.2 and 26+/-21 microM; and total brain concentrations were 7.2+/-0.3 and 23+/-0.3 microM in wild-type and mdr1a (-/-) mice, respectively. Plasma concentrations were similar (18.4+/-0.7 and 17.9+/-0.5 microM, respectively). In conclusion, sparfloxacin enters the brain poorly mainly because of P-glycoprotein activity at the blood-brain barrier.

4-Quinolones↗

PubMed2000

Relationship between permeability status of the blood-brain barrier and in vitro permeability coefficient of a drug.

OBJECTIVE: The aim was to test the hypothesis that the assessment of basal and drug-induced changes in permeability of the blood-brain barrier (BBB) during in vitro drug transport assays is essential for an accurate estimation of the permeability coefficient of a drug. METHODS: An in vitro BBB model was used, comprising of brain capillary endothelial cells (BCEC) and astrocytes co-cultured on semi-permeable filter inserts. Experiments were performed under control and challenged experimental circumstances, induced to simulate drug effects. The apparent BBB permeability coefficient for two markers for paracellular drug transport, sodium fluorescein (P(app,FLU), M(w) 376 Da) and FITC-labeled dextran (P(app,FD4), M(w) 4 kDa), was determined. Transendothelial electrical resistance (TEER) was used to quantify basal and (simulated) drug-induced changes in permeability of the in vitro BBB. The relationship between P(app) and TEER was determined. Drug effects were simulated by exposure to physiologically active endogenous and exogenous substances (i.e., histamine, deferroxamine mesylate, adrenaline, noradrenaline, bradykinin, vinblastine, sodium nitroprusside and lipopolysaccharide). RESULTS: P(app,FLU) and P(app,FD4) in control experiments varied from 1.6 up to 17.6 (10(-6)cm/s) and 0.3 up to 7. 3 (10(-6)cm/s), respectively; while for individual filters P(app, FLU) was 4 times higher than P(app,FD4) (R(2)=0.97). As long as TEER remained above 131.Omega cm(2) for FLU or 122.Omega cm(2) for FD4 during the transport assay, P(app) remained independent from the basal permeability of the in vitro BBB. Below these TEER values, P(app) increased exponentially. This nonlinear relationship between basal BBB permeability and P(app) was described by a one-phase exponential decay model. From this model the BBB permeability status independent permeability coefficients for FLU and FD4 (P(FLU) and P(FD4)) were estimated to be 2.2+/-0.1 and 0.48+/-0.03 (10(-6)cm/s), respectively. In the experimentally challenged experiments, a reliable indication for P(FLU) and P(FD4) could be estimated only after the (simulated) drug-induced change in BBB permeability was taken into account. CONCLUSIONS: The assessment of basal BBB permeability status during drug transport assays was essential for an accurate estimation of the in vitro permeability coefficient of a drug. To accurately extrapolate the in vitro permeability coefficient of a drug to the in vivo situation, it is essential that drug-induced changes in the in vitro BBB permeability during the drug transport assay are determined.

Animals↗