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  • 1
    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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  • 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
    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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  • 4
    Electronic Resource
    Electronic Resource
    The Use of Intracerebral Microdialysis to Determine Changes in Blood-Brain Barrier Transport Characteristics (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 129-133 
    Details
    ISSN: 1573-904X
    Keywords: intracerebral microdialysis ; blood-brain barrier ; hypertonic opening ; atenolol, pharmacokinetics ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The aim of this study was to determine whether changes in the transport of drugs into the brain could be determined by in vivo intracerebral microdialysis. Atenolol was used as a model drug to determine blood-brain barrier (BBB) transport characteristics. In rats, unilateral opening of the blood-brain barrier was achieved by infusion of hyperosmolar mannitol (25%, w/v) into the left internal carotid artery. BBB transport, expressed as the ratio of the area under the curve (AUC) of atenolol in brain extracellular fluid over plasma, was three times higher for the mannitol treated hemisphere as compared with the contralateral brain or after infusion of saline, being (mean ± SEM) 0.094 ± 0.024 (n = 16), 0.029 ± 0.007 (n = 12) and 0.030 ± 0.009 (n = 12) respectively. Further evaluation of the data indicated that for experiments performed in the morning the mannitol infusion had little effect on the extent of transport of atenolol into the brain, while in the afternoon BBB transport was about 10-fold higher than in the contralateral and saline group. The mean “afternoon” ratios ± SEM were 0.155 ± 0.038 (n = 8), 0.012 ± 0.003 (n = 6) and 0.018 ± 0.006 (n = 6) respectively. It is concluded that intracerebral microdialysis is capable of revealing changes in BBB transport and regional and time-dependent differences in drug levels can be demonstrated with the use of this technique.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016207208406
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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
    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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  • 8
    Electronic Resource
    Electronic Resource
    Rectal Absorption Enhancement of Des-Enkephalin-γ-Endorphin (DEγE) by Medium-Chain Glycerides and EDTA in Conscious Rats (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 91-95 
    Details
    ISSN: 1573-904X
    Keywords: absorption enhancement ; neuropeptides ; des-enkephalin-γ-endorphin ; medium-chain glycerides ; EDTA ; peptidase inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The stability of the neuroleptic peptide des-enkephalin-γ-endorphin (DEγE; Org 5878) in the rectal lumen and the rectal bioavailability of DEγE were investigated in conscious rats. Furthermore, the influence of peptidase inhibition, peptidase saturation, and absorption enhancement on DEγE bio-availability were evaluated. Na2EDTA (0.25%, w/v) prolonged the degradation half-life of DEγE in the ligated colon from 33 ± 7 to 93 ± 45 min. Without adjuvant, tritium-labeled DEγE was absorbed from the rat rectum to a very low extent (0–4%). After administration of an excess of unlabeled DEγE or with Na2EDTA, comparable results were obtained. The medium-chain glyceride preparation MGK markedly enhanced the rectal DEγE bioavailability, up to 8–20%, which was further increased to 10–44% by coadministration of Na2EDTA. No substantial influence of varying the rectal delivery rate was observed. The results suggest that absorption enhancement and enzyme inhibition both are essential for effective increase of rectal peptide bioavailability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015864022305
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  • 9
    Electronic Resource
    Electronic Resource
    Absorption Enhancement of Rectally Infused Insulin by Sodium Tauro-24,25-Dihydrofusidate (STDHF) in Rats (1990)
    Springer
    Pharmaceutical research 7 (1990), S. 180-183 
    Details
    ISSN: 1573-904X
    Keywords: insulin ; absorption ; sodium tauro-24,25-dihydrofusidate ; rectum ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bile salt derivative sodium tauro-24,25-dihydrofusidate (STDHF) has been reported to promote nasal absorption of insulin. In the present study the effect of STDHF on rectal insulin absorption was investigated in rats. At concentrations of 1 and 4% (w/v) it enhanced insulin bioavailability from 0.2 ± 0.2 (control) to 4.2 ± 3.2 and 6.7 ± 2.1%, respectively, as assessed by radioimmunoassay. Insulin preparations with STDHF reduced blood glucose concentrations considerably in a concentration-dependent way. Coadministration of STDHF with Na2EDTA (0.25%, w/v) tended to increase further insulin bioavailability and hypoglycemic response. Varying the site of rectal administration did not influence these parameters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015837004307
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  • 10
    Electronic Resource
    Electronic Resource
    Stereoselective Transport of Baclofen Across the Blood–Brain Barrier in Rats as Determined by the Unit Impulse Response Methodology (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 259-262 
    Details
    ISSN: 1573-904X
    Keywords: baclofen ; blood–brain barrier transport ; enantiomers ; transport ; stereoselective
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The blood–brain barrier transport characteristics of racemic baclofen and the separate R- and S-enantiomers have been determined in vivo in rats by using the unit impulse response methodology. Transport rate was determined as blood–brain barrier clearance, the volume of plasma per unit time cleared of baclofen by transport across the blood–brain barrier. Plasma elimination kinetics and CSF elimination kinetics did not differ among racemic baclofen and the R-and S-enantiomers. Transport of each compound could be described by a linear V(t] curve, suggesting the absence of saturable transport processes in the concentration range studied. However, for R-baclofen the blood–brain barrier clearance (4.7 ± 1.0 µl/min, mean ± SE; n = 6) and cumulative transported amount (0.085 ± 0.007%; n = 6) were significantly higher than these values for the S-enantiomer (1.1 ± 0.3 µl/min, 0.031 ± 0.005%; n = 6) and racemic baclofen (1.0 ± 0.1 µl/min, 0.036 ± 0.003%; n = 6). These findings indicate that there is stereoselective transport of baclofen across the blood–brain barrier.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015812725011
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