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  • 1
    Electronic Resource
    Electronic Resource
    Quantification and Visualization of the Transport of Octreotide, a Somatostatin Analogue, Across Monolayers of Cerebrovascular Endothelial Cells (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 442-448 
    Details
    ISSN: 1573-904X
    Keywords: octreotide ; somatostatin analogue ; SMS 201-995 ; peptides ; blood–brain barrier ; transport ; visualization ; confocal laser scanning microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Confocal laser scanning microscopy (CLSM) was used to quantify and visualize the transport of the octapeptide and somatostatin analogue, octreotide (SMS 201-995, Sandostatin), across monolayers of bovine cerebrovascular endothelial cells, an in vitro model of the blood–brain barrier. The concentrations of octreotide and its conjugates in the cell culture medium were determined by radioimmunoassay (RIA). Two fluorescent conjugates of octreotide (FITC- and NBD-octreotide) were used to obtain CLSM images. The peptides did not undergo significant degradation in the presence of brain endothelial cell monolayers. The transport rate of octreotide expressed as clearance (Cl) and endothelial permeability (P e) did not depend on either the initial concentration (between 10 nM and 1 µM) or the site of administration (luminal or abluminal side of the mono-layer), indicating the absence of saturable and/or asymmetrical transport mechanisms. The P e of octreotide and that of the paracellular permeability marker fluorescein correlated well. Although the conjugates are more lipophilic than octreotide itself, they exhibited lower Cl and P e, values probably because of their larger molecular size. On the CLSM images, FITC-octreotide was present only in the intercellular space, while the cells did not exhibit detectable fluorescence. Transport studies and CLSM images suggest that octreotide passes the endothelial monolayer primarily via the paracellular route without significant contribution of carrier-mediated transport.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018929508018
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  • 2
    Electronic Resource
    Electronic Resource
    In Vitro and in Vivo Transport of Zidovudine (AZT) Across the Blood–Brain Barrier and the Effect of Transport Inhibitors (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 324-330 
    Details
    ISSN: 1573-904X
    Keywords: azidothymidine (AZT) ; central nervous system ; blood–brain barrier ; brain ; cerebrospinal fluid ; transport ; acquired immunodeficiency syndrome (AIDS)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The transport of the antiviral nucleoside analogue zidovudine (3′-azido-3′-deoxythymidine; AZT) into the central nervous system (CNS) was characterized in vitro and in vivo. The in vitro model consisted of primary cultures of isolated bovine capillary endothelial cells. The transport rate of AZT across the monolayer, expressed as endothelial permeability P, was determined following luminal and abluminal administration. P did not differ between the two administration sites (luminal, 1.65 ± 0.44 cm/min/103; abluminal, 1.63 ± 0.28 cm/min/103). The transport of AZT across the endothelial cell monolayer was found to be concentration independent in the range between 0.4 and 50 µg/mL. AZT transport was not affected by pre-treatment of the cells with either metabolic inhibitors (DODG and DODG/NaN3) or probenecid. This suggests that AZT passes the monolayer mainly by passive diffusion. The in vivo transport of AZT across the blood–brain barrier and the blood–CSF barrier was studied in male Wistar rats after coadministration of potential inhibitors of active transport of AZT: probenecid (organic anion transport) and thymidine (nucleoside transport). Intracerebroventricular and intravenous coadministration of probenecid caused a significant (P 〈 0.001) increase in the CSF/plasma concentration ratio compared to the control phase, indicating that the organic anion carrier is involved in AZT transport from CSF to blood. Since there was no effect of probenecid on the transport of AZT in vitro, it is suggested that this carrier is located at the choroid plexus. Coadministration of thymidine did not affect the CSF/plasma concentration ratio, suggesting that a nucleoside carrier system is not involved in AZT transport into or out of the CNS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018932213953
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  • 3
    Electronic Resource
    Electronic Resource
    HANS BUNDGAARD IN MEMORIAM (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 164-164 
    Details
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018914205969
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  • 4
    Electronic Resource
    Electronic Resource
    The Use of Intracerebral Microdialysis for the Determination of Pharmacokinetic Profiles of Anticancer Drugs in Tumor-Bearing Rat Brain (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1924-1931 
    Details
    ISSN: 1573-904X
    Keywords: Microdialysis: experimental brain tumor ; pharmacokinetic ; anticancer drugs ; methotrexate ; histology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The use of intracerebral microdialysis as a tool to measure the penetration of anticancer agents in brain tumor was investigated. Methods. Following intravenous (iv) administration of 75 mg/kg. concentration-time profiles of methotrexate (MTX) were determined in brain cortical dialysate and in plasma. The individual ratio of the area under the curve of MTX in brain dialysate over that in plasma (MTX penetration) was determined in normal brain, in tumor-bearing brain and in brain after sham tumor implantation. Individual brains were examined histologically on the presence of tumor, as well as for other factors that might influence local MTX penetration. Histological scores were related to the individual data on penetration of MTX. Results. MTX penetration values were higher in cortical brain at the site of the tumor, as compared to the levels measured in normal or sham implanted brain (mean increase to 250 %). In the cortical brain contralateral to the tumor, MTX penetration values were found to be lower than in normal brain (mean reduction of 65 %). Furthermore, it appeared that in the absence of tumor tissue, the presence of exudate around the probe was independently associated with increased penetration of MTX into the brain. Conclusions. Tumor tissue appeared to be the most important parameter in changing local MTX penetration in brain after tumor implantation. In general, it is anticipated that intracerebral microdialysis combined with histological examination can be used to investigate effects of brain tumor presence on regional (periprobe) penetration of anticancer drugs into the brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016239822287
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  • 5
    Electronic Resource
    Electronic Resource
    Transport of a Hydrophilic Compound into the Cerebrospinal Fluid During Experimental Allergic Encephalomyelitis and After Lipopolysaccharide Administration (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1932-1936 
    Details
    ISSN: 1573-904X
    Keywords: multiple sclerosis ; experimental allergic encephalomyelitis ; lipopolysaccharide ; blood-brain barrier
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The transport of the hydrophilic model compound sodium fluorescein into the cerebrospinal fluid (CSF) of rats was studied during experimental allergic encephalomyelitis (EAE), as a model for local central nervous system (CNS) inflammatory disease, and after a single injection of a pyrogenic dose of lipopolysaccharide (LPS), as a model for a general inflammation. Methods. Transport of sodium fluorescein was measured by means of serial CSF and plasma sampling. Transport of this hydrophilic model compound was studied in Lewis rats suffering from EAA and three hours after LPS administration in male Wistar rats. Results. During acute EAE, sodium fluorescein concentrations in the CSF increased twofold compared to control animals, whereas plasma kinetics were comparable within both groups. After i.v. LPS administration, however, plasma as well as CSF kinetic parameters of sodium fluorescein concentration were significantly changed from those seen in control animals. Transport of sodium fluorescein from plasma into the CSF was calculated as the ratio Area Under the Curve (AUC) CSF/ AUCPLASMA. During acute EAE this ratio increased 2-fold compared to control animals, whereas after i.v. LPS administration it was not significantly different from the one obtained in control animals. Conclusions. These results suggest an opening of the blood-brain barrier (BBB) during a cerebral inflammatory response, like acute EAE, but not after LPS administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016291806357
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  • 6
    Electronic Resource
    Electronic Resource
    BBB Transport and P-glycoprotein Functionality Using MDR1A (-/-) and Wild-Type Mice. Total Brain Versus Microdialysis Concentration Profiles of Rhodamine-123 (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1657-1665 
    Details
    ISSN: 1573-904X
    Keywords: intracerebral microdialysis ; blood-brain barrier ; mdrla (-/-) mice ; in vivo recovery ; rhodamine-123 ; P-glycoprotein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect of P-glycoprotein (Pgp) on brain distribution using mdrla (-/-) mice was investigated. Methods. Fluorescein (Flu) and FD-4 were used to check whether blood-brain barrier (BBB) integrity was maintained in mdrla (-/-) mice. The Pgp substrate rhodamine-123 (R123) was infused and total brain, blood and brain microdialysate concentrations in mdrla (-/-) mice and wild-type mice were compared. Results. Maintenance of BBB integrity was indicated by equal total brain/blood ratios of Flu and FD-4 in both mice types. R123 concentrations in brain after i.v. infusion were about 4-fold higher in mdrla (-/-) than in wild-type mice (P 〈 0.05), without changes in blood levels. After microdialysis experiments the same results were found, excluding artifacts in the interpretation of Pgp functionality by the use of this technique. However the 4-fold ratio in brain was not reflected in corresponding microdialysates. No local differences of R123 in the brain were found. By the no-net-flux method in vivo recovery appeared to 4.6-fold lower in mdrla (-/-) mice compared with wild-type mice. Conclusions. Pgp plays an important role in R123 distribution into the brain. Using intracerebral microdialysis, changes in in vivo recovery by the absence or inhibition of Pgp (or active efflux in general) need to be considered carefully.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011988024295
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  • 7
    Electronic Resource
    Electronic Resource
    Brain Penetration and In Vivo Recovery of NMDA Receptor Antagonists Amantadine and Memantine: A Quantitative Microdialysis Study (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 637-642 
    Details
    ISSN: 1573-904X
    Keywords: aminoadamantanes ; in vivo recovery ; microdialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine free brain concentrations of the clinically used uncompetitive NMDA antagonists memantine and amantadine using microdialysis corrected for in vivo recovery in relations to serum, CSF and brain tissue levels and their in vitro potency at NMDA receptors. Methods. Microdialysis corrected for in vivo recovery was used to determine brain ECF concentrations after steady-state administration of either memantine or amantadine. Additionally CSF, serum, and brain tissue were analyzed. Results. Following 7 days of infusion of memantine or amantadine (20 and 100 mg/kg/day respectively) whole brain concentrations were 44-and 16-fold higher than free concentrations in serum respectively. The free brain ECF concentration of memantine (0.83 ± 0.05 μM) was comparable to free serum and CSF concentrations. In case of amantadine, it was lower. A higher in vivo than in vitro recovery was found for memantine. Conclusions. At clinically relevant doses memantine reaches a brain ECF concentration in range of its affinity for the NMDA receptor and close to its free serum concentration. This is not the case for amantadine and different mechanisms of action may be operational.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018856020583
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  • 8
    Electronic Resource
    Electronic Resource
    Absorption Enhancement of Rectally Infused Cefoxitin Sodium by Medium-Chain Fatty Acids in Conscious Rats: Concentration–Effect Relationship (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 453-456 
    Details
    ISSN: 1573-904X
    Keywords: rectal absorption enhancement ; cefoxitin ; fatty acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The objective of this study was to assess the relative absorption promoting potency in terms of concentration–effect relationships of the medium-chain fatty acids hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid in conscious rats, using cefoxitin sodium as the rectally delivered model compound. Rectal uptake of cefoxitin, which was absorbed to a limited extent without enhancer (30 ± 25%), proved to be significantly enhanced by 2.0 M sodium hexanoate, 0.69 M sodium octanoate, and 0.22 M sodium decanoate, resulting in mean bioavailabilities of 102 ± 24, 68 ± 25, and 68 ± 10%, respectively. Thus, increasing fatty acid chain length results in increased enhancing potency from hexanoic acid to decanoic acid. However, using dodecanoate a statistically significant effect could not be reached, because of its limited aqueous solubility. Optimal chain length for absorption enhancement by medium-chain fatty acids is probably determined by interplay of intrinsic effects on mucosal permeability and solubility of the medium-chain fatty acid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015948720256
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  • 9
    Electronic Resource
    Electronic Resource
    Site Specific Rectal Drug Administration in Man with an Osmotic System: Influence on “First-Pass” Elimination of Lidocaine (1984)
    Springer
    Pharmaceutical research 1 (1984), S. 129-134 
    Details
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Lidocaine was administered to healthy volunteers at different sites in the rectum. Unchanged drug and monoethylglycinexylidide (MEGX) concentrations were measured in plasma with a newly developed gas chromatographic method. Lidocaine was given rectally by means of an osmotic system (Osmet®) which delivered 25 mg/h at zero-order rate. In a pilot experiment in two subjects it was shown that lidocaine administration close to the anus for 5 h resulted in higher lidocaine plasma levels as compared to administration at 15 cm from the anus. Six other subjects participated in three separate experiments, in which lidocaine was administered rectally close to the anus and at 7.5 and 15 cm from the anus. A zero-order infusion plasma level profile was found for both the parent compound and its metabolite. The MEGX/lidocaine plasma concentration ratio was calculated for all experiments. After administration most proximal to the anus the mean metabolite/parent drug concentration ratio was significantly less than that obtained after administration at 15 cm from the anus, whereas at approximately 7.5 cm from the anus the values were in-between. Comparison of the AUC lidocaine/AUC MEGX ratios gave similar results; the highest value, 3.2 ± 1.3 (mean ± S. D.), was found after administration close to the anus, while at 15 cm from the anus the ratio was 1.6 ± 0.3 (p 〈 0.01). The terminal elimination half-lives of lidocaine and MEGX did not differ for the three sites of administration, and the mean values were 110 and 180 min respectively. The results of this study demonstrate that the site of drug administration in the human rectum determines the degree of hepatic “first-pass” elimination of high-clearance drugs. Maximal avoidance of presystemic elimination is achieved when administration takes place close to the anus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016380104424
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  • 10
    Electronic Resource
    Electronic Resource
    Avoidance of “First-Pass” Elimination of Rectally Administered Propranolol in Relation to the Site of Absorption in Rats (1984)
    Springer
    Pharmaceutical research 1 (1984), S. 164-168 
    Details
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The extent of “first-pass” elimination of racemic propranolol and dextropropranolol in doses of 0.25 or 0.50 mg was investigated in relation to the site of drug administration in the rectum of rats. The compounds were given orally, i.v., and rectally at distances of 2 and 1 cm from and directly at the anus by low volume zero-order 30 min infusion. Unchanged propranolol was determined in blood, and propranolol and three metabolites were measured in urine. The systemic availability of propranolol after oral administration was approximately 6 %. Rectal administration at 2 cm, at 1 cm and directly at the anus (0.2 cm) gave two, three and six times higher values, respectively. The more distal application site produced urinary metabolite profiles that were comparable to those observed after oral administration, while application directly at the anus was similar to i.v. dosing. In all experiments log-linear elimination phases with comparable elimination half-lives (range 12–18 min) were found, except with the 0.50 mg dose after i.v. and rectal administration close to the anus which showed a non-linear profile. The mean systemic availability after rectal administration of 0.25 mg dextro-propranolol close to the anus was 50 and 64 % as compared to a 0.25 and 0.125 mg i.v. dose, respectively. The rectal route may be used for propranolol to partially prevent hepatic first-pass metabolism. However, avoidance of presys-temic elimination is maximal only in the immediate vicinity of the anus as the venous blood supply of the upper part of the rectum of rats appears to be connected to the portal system and the lower part to the general circulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016396508058
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