Biomedical subjects

Chang-Koo Shim

Publications and source records attributed to Chang-Koo Shim.

36 records · Page 2Linked to original sources

PubMed2005

Limited role of P-glycoprotein in the intestinal absorption of cyclosporin A.

The contribution of P-glycoprotein (P-gp) to the intestinal absorption of cyclosporin A (CsA) was investigated by comparing the in vivo pharmacokinetics of CsA in P-gp knockout mice versus wild-type mice following both oral and intravenous administration and by examining the transport of CsA across Caco-2 cell monolayers. The apparent oral bioavailability of CsA in P-gp knockout mice was 1.55-fold larger than in wild-type mice, leading to an apparent absolute bioavailability of 41.8%. A concentration dependent efflux transport of CsA across Caco-2 cell monolayers was found, which exhibited saturation at a CsA concentration of 1 muM. These results suggest that the involvement of P-gp in the intestinal absorption of CsA is not as profound as was previously thought.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Saturable distribution of tacrine into the striatal extracellular fluid of the rat: evidence of involvement of multiple organic cation transporters in the transport.

The kinetics and mechanism by which tacrine is distributed in the rat brain were examined. Tacrine levels in plasma and striatal extracellular fluid were used to evaluate the pharmacokinetics of this process. The K(D,brain) was decreased with the dose for tacrine, indicating that the distribution to the brain is saturable. The uptake of organic cations such as choline, 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), and carnitine was inhibited by the addition of tacrine to cultures of mouse immortalized brain capillary endothelial cells. In addition, the apical to basal transport and basal to apical transport of tacrine were inhibited by the addition of organic cations to cultures of LLC-PK1 cells, suggesting that tacrine transport across the blood-brain barrier (BBB) is mediated by organic cation transport system(s). Consistent with the in vitro results, a standard reverse transcription-polymerase chain reaction procedure was able to amplify the message of mOCT2 and mOCTN2, but not mOCT1, in MBEC4 (mouse brain microvessel endothelial cell line 4) cells. Similarly, mRNAs for rOCT2 and rOCTN2 were present in representative rat brain samples. To determine whether OCT2 and/or OCTN2 transport tacrine, these transporters were cloned and then transfected in SK-HEP1 and HEK 293 cells. The uptake of choline, MPP, and TEA was inhibited by the presence of tacrine in rOCT2-expressing SK-HEP1 cells, whereas the uptake of carnitine was inhibited by the presence of tacrine in rOCTN2-expressing HEK 293 cells. Collectively, these observations suggest that the transport of tacrine across the BBB is mediated, at least in part, by multiple organic cation transport systems in rats.

Animals↗

PubMed2004

Pharmacokinetic characterization of dehydroevodiamine in the rat brain.

The objective of this study was to examine the kinetics of the distribution of dehydroevodiamine (DHED) in the rat brain. After an intravenous infusion of 15 min (dose of 1-10 mg/kg), the temporal profiles of the plasma levels of DHED declined in a multiexponential manner. Moment analysis indicated that the clearance and steady-state volume of distribution for DHED were not statistically different with the dose, indicating that the pharmacokinetics for DHED is linear in the range examined. Nonlinear regression analysis of DHED concentrations in the plasma and the brain revealed that the linear kinetics into and out from the brain reasonably described the data and that the clearances for influx into and efflux from the brain were comparable. Transport clearances for DHED across MBEC4 monolayers, an in vitro model of the blood-brain barrier, were also comparable for influx and efflux, and were independent of the medium concentration. The concentration of DHED in cerebrospinal fluid was negligible compared with that found in plasma, indicating that the drug is not primarily distributed to the brain via the blood-cerebrospinal fluid barrier. These observations indicate that DHED is transported from the systemic circulation to the brain via the blood-brain barrier by linear kinetics.

Algorithms↗

PubMed2003

The suppressed expression and functional activity of hepatic P-glycoprotein in rats with protein-calorie malnutrition.

The effect of protein-calorie malnutrition (PCM) on the expression and functional activity of P-glycoprotein (P-gp) in the liver of rats was examined. Control protein diets and protein-restricted diets were fed to Sprague-Dawley rats for 4 weeks, and the expression of P-gp in the liver (Western blot), in vitro uptake of a representative substrate of P-gp, daunomycin, into canalicular liver plasma membrane (cLPM) vesicles, and in vivo canalicular excretion of daunomycin were compared between the control and PCM rats. The expression of P-gp in the cLPM vesicles was decreased (22%, p < 0.05) by PCM. Consistent with this result, the in vitro uptake rate (V(max)) was decreased (35%, p < 0.05) by PCM, with constant affinity (K(m)), for the carrier-mediated uptake of daunomycin into cLPM vesicles, resulting in a 33% (p < 0.05) decrease in the intrinsic uptake clearance (CL(int)). The in vivo canalicular excretion clearance (CL(exc)) of daunomycin was also decreased by 79% (p < 0.01) in PCM rats, but the degree was more severe than would be expected from the 22% decrease in the expression of P-gp and the 33% decrease in the uptake of daunomycin (CL(int)). The hepatic level of adenosine 5'-triphosphate, which was decreased by 60% (p < 0.01) in PCM rats, might have contributed to this severe decrease in CL(exc). In summary, the canalicular excretion of P-gp substrates, such as daunomycin, might be reduced in patients with PCM via a mechanism involving the suppression of the expression of P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Effect of excipients on the stability and transport of recombinant human epidermal growth factor (rhEGF) across Caco-2 cell monolayers.

The effect of sixteen excipients on the transport of recombinant human epidermal growth factor (rhEGF) across Caco-2 cell monolayers was examined at 37 degrees C. The apparent apical to basolateral (A-B) permeability (Papp) of 30 microM rhEGF was 8.15 x 10(-7) cm/sec, indicative of a poor level of absorption in the GI tract. The Papp was 1.7- and 6.3-fold greater than the Papp in the basolateral to apical (B-A) direction and the A-B permeability of mannitol, respectively, and decreased dramatically to a negligible level at 4 degrees C, consistent with a receptor mediated transcytosis of rhEGF. The stability of rhEGF was very poor, undergoing more than 85% degradation in 2 h in the transport medium at 37 degrees C. A significant increase in the Papp could be achieved by the addition of certain excipients, as exemplified by 23, 21, 20 and 16-fold increases, in the presence of sodium taurochenodeoxycholate (NaTCDC), sodium taurodeoxycholate (NaTDC), sodium glycodeoxycholate (NaGDC) and sodium laurylsulfate (SLS) (all at a concentration of 1% w/v), respectively. A significant increase in stability could also be achieved by the addition of some of the excipients, as represented by 1% SLS, which nearly completely stabilized the rhEGF. Unfortunately, however, an increase in the Papp of rhEGF could not be achieved without a simultaneous and extensive decrease in the integrity of the cell membranes. Thus, more efficient excipients, that specifically enhance the permeation of rhEGF and do not alter the membrane integrity, should be pursued in order to safely enhance the permeation of rhEGF.

Absorption↗

PubMed2003

Kinetic analysis about the bidirectional transport of 1-anilino-8-naphthalene sulfonate (ANS) by isolated rat hepatocytes.

The purpose of the present study was to investigate the bidirectional transport of 1-anilino-8-naphthalene sulfonate (ANS) using isolated rat hepatocytes. The initial uptake rate of ANS by isolated hepatocytes was determined. The uptake process of ANS was saturable, with a Km of 29.1 +/- 3.2 microM and Vmax of 2.9 +/- 0.1 mmol/min/mg protein. Subsequently, the initial efflux rate of ANS from isolated hepatocytes was determined by resuspending preloaded cells to 3.0% (w/v) BSA buffer. The efflux process for total ANS revealed a little saturability. The mean value of the efflux clearance was 2.2 +/- 0.1 microL/min/mg protein. The efflux rate of ANS from hepatocytes was markedly decreased at 4 degrees C, indicating that the apparent efflux of ANS might not be attributed to the release of ANS bound to the cell surface, but to the efflux of ANS from intracellular space. The efflux clearance was furthermore corrected for the unbound intracellular ANS concentration on the basis of its binding parameters to cytosol. The relation between efflux rate and unbound ANS concentration was fitted well to the Michaelis-Menten equation with a saturable and a nonsaturable components. The Vmax and Km values were 0.54 mmol/min/mg protein, and 10.0 microM, respectively. Based on the comparison of the ratios of Vmax to Km (Vmax/Km) corresponding to the transport clearance, the influx clearance was two times higher than the efflux clearance. Together with our preliminary studies that ATP suppression in hepatocytes substantially inhibited ANS influx rate, we concluded that the hepatic uptake of ANS is actively taken up into hepatocytes via the carrier mediated transport system.

Anilino Naphthalenesulfonates↗

PubMed2003

Contribution of ion-pair complexation with bile salts to the transport of organic cations across LLC-PK1 cell monolayers.

PURPOSE: To examine the effect of ion-pair complexation with endogenous bile salts on the transport of organic cations (OCs) across LLC-PK1 cell monolayers. METHODS: The transport of tributylmethyl-ammonium (TBuMA) and triethylmethylammonium (TEMA) across the cell monolayer was measured in the presence of taurodeoxycholate (TDC), an endogenous organic anion that forms an ion-pair complex with TBuMA, but not with TEMA. RESULTS: Under proton gradient conditions (i.e., pH 6.0 apical/pH 7.4 basal), the above OCs exhibited similar transport charactersistics, consistent with the well-established OC/H+ antiporter, and the presence of TDC had no measurable effect on the transport of these OCs. Under pH-equilibrated conditions (i.e., pH 7.4 apical/pH 7.4 basal); however. basal to apical transport of TBuMA, not that of TEMA, was increased in the presence of TDC, probably as a result of the formation of a lipophilic ion-pair complex between TBuMA and TDC. The transport and efflux of the TBuMA-TDC complex across the apical membrane of the cell was inhibited by representative substrates of the P-glycoprotein (P-gp), indicating the involvement of P-gp in this process. The increased affinity of the ion-pair complex to P-gp is consistent with a mechanism involving increased transport. CONCLUSION: In cases where there is no proton gradient between the plasma and urine, the formation of lipophilic ion-pair complexes in the kidney with endogenous bile salts might be involved in the in vivo urinary excretion of large Mw OCs, such as TBuMA.

Animals↗

PubMed2003

Multiple alterations of canalicular membrane transport activities in rats with CCl(4)-induced hepatic injury.

The influence of CCl(4)-induced experimental hepatic injury (CCl(4)-EHI) on the expression and transport activities of primary active transporters on the canalicular membrane, including P-glycoprotein (P-gp), a bile salt export pump (Bsep) and a multidrug resistance associated protein2 (Mrp2), was assessed. CCl(4)-EHI was induced by an intraperitoneal injection of CCl(4) to rats at a dose of 1 ml/kg 24 h prior to the preparation of canalicular liver plasma membrane (cLPM) vesicles and pharmacokinetic studies. The expression of each transporter was measured for the vesicles via Western blot analysis at 6, 12, 24, 36, and 48 h after the injection of CCl(4). The in vivo canalicular excretion clearance (CL(exc)) of [(3)H]daunomycin, [(3)H]taurocholate and [(3)H]17beta-estradiol-17beta-D-glucuronide (E(2)17betaG), representative substrates of P-gp, Bsep, and Mrp2, respectively, was determined following an i.v. infusion to rats. The uptake of each substrate into cLPM vesicles in the presence of ATP was also measured by a rapid filtration technique. As the result of the CCl(4)-EHI, the protein level of transporters was altered as a function of time in multiple manners; it was increased by 3.6-fold for P-gp, unchanged for Bsep, and decreased by 73% for Mrp2 at 24 h. The in vivo CL(exc) and the intrinsic uptake clearance into cLPM vesicles (CL(int)) at 24 h after the CCl(4) injection (CCl(4)-EHI(24 h)) were also influenced by the EHI in a similar manner; they were increased by 1.8- and 1.9-fold for daunomycin, unchanged for taurocholate, and decreased by 41 and 39% for E(2)17betaG, respectively, consistent with multiple alterations in the expression of the relevant transporters.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Preparation and evaluation of proliposomes containing salmon calcitonin.

Salmon calcitonin (sCT)-containing proliposomes were prepared by penetrating a methanol-chloroformic solution of sCT and phosphatidylcholine (PC) into microporous sorbitol particles, followed by vacuum evaporation of the solvent. As a result, sCT proliposomes with free-flowing flowability were obtained. On contact with water, the proliposomes were rapidly converted into a liposomal dispersion, in which a certain amount of sCT was entrapped by the liposomes. The apparent permeability of sCT across Caco-2 cell monolayers was increased as the result of incorporating sCT into the proliposomes, suggesting that the pharmacokinetics of sCT would be modified through the administration of proliposomes. This is the first study that reports the successful loading of sCT, a protein drug, in proliposomes. The development of various dosage forms of sCT, especially solid dosage forms, appears be feasible using proliposomes.

Caco-2 Cells↗

PubMed2002

Simple liquid chromatography-electrospray ionization mass spectrometry method for the routine determination of salmon calcitonin in serum.

A simple liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) method was developed for the quantification of salmon calcitonin (sCT) in serum. Serum samples from rats and dogs were deproteinized and freeze-dried. The residue was then reconstituted with 57% acetonitrile in water containing 0.1% trifluoroacetic acid and 0.005% benzalkonium chloride. A 20-microl aliquot of the reconstituted solution was injected onto a polymer based RP-C18 column, The outlet was connected to an ion-trap mass spectrometer equipped with an ESI source, and spectra were recorded in a positive-ion, selected-ion monitoring mode. The limit of quantification of the method was 10 ng/ml. Biexponential curves were observed for the temporal serum concentration of sCT following intravenous administration of sCT to rats (100 microg/kg) and dogs (250 microg/kg), resulting in reasonable pharmacokinetic parameters. The present method appears applicable to routine analysis of serum sCT in pharmacokinetic studies with good selectivity, accuracy and precision.

Animals↗

PubMed2002

Altered metabolism of orally administered loxoprofen in human subjects after an oral administration of loxoprofen for three consecutive days followed by a seven-day washout.

The effect of pretreatment (i.e., oral administration of loxoprofen for 3 consecutive days followed by a 7-day washout) on the pharmacokinetics and metabolism of the drug was studied in humans. In a control study, a Loxonin tablet (60 mg as loxoprofen anhydrous) was administered orally to 6 healthy male Korean subjects. In a pretreatment study, a Loxonin tablet was administered orally to the subjects once daily for 3 consecutive days. On the 10(th) day, a Loxonin tablet was administered orally to the subjects, and the concentrations of loxoprofen and the trans- and cis-alcohol metabolites in the plasma and urine were measured as a function of time. Using this pretreatment, the area under the curve (AUC) of the trans-alcohol metabolite of loxoprofen in the plasma, but not those of loxoprofen and the cis-alcohol metabolite, was increased (1.5-fold, p < 0.05), leading to increased contribution of the trans-alcohol metabolite to the total urinary recovery of loxoprofen (1.3-fold, p < 0.05). The urinary recovery of total metabolites, which was largely (> 90%) comprised of conjugate metabolites, was also increased as a result of the pretreatment (1.5-fold, p < 0.05). These results indicate that stereoselective reduction to trans-alcohol metabolites as well as the phase II metabolism of loxoprofen may be increased by such a pretreatment in human subjects.

Administration, Oral↗

PubMed2002

P-glycoprotein-mediated transport of berberine across Caco-2 cell monolayers.

The objective of this study was to investigate the mechanisms by which berberine is transported in the secretory and absorptive directions across Caco-2 cell monolayers. The basolateral-to-apical (B-A) flux was 30-fold greater than the apical-to-basolateral flux and temperature dependent (i.e., drastic decrease at 4 degrees C compared with 37 degrees C). The above results suggest the involvement of a carrier-mediated active transport mechanism for the B-A transport of berberine. However, no significant concentration dependency for the permeability (P(app)) of berberine was observed for B-A transport over a concentration range of 5-300 microM, indicating that the K(m) value of berberine for the carrier system is greater than 300 microM. Well-documented P-glycoprotein (P-gp) substrates such as verapamil, daunomycin, and rhodamine123 inhibited the B-A flux of berberine, whereas tetraethylammonium and taurocholate did not, suggesting that P-gp is involved in the transport. For the case of daunomycin, the B-A flux, but not the apical-to-basolateral flux, was significantly increased after pretreatment of the cell monolayers with berberine. In addition, the uptake of 1 microM daunomycin into Caco-2 cells was decreased as a result of this pretreatment. These results suggest that the repeated administration of berberine may up-regulate P-gp functions in Caco-2 cells. If this occurs in the gastrointestinal epithelial cells, the repeated administration of berberine may reduce the gastrointestinal absorption of P-gp substrates including chemotherapeutic agents such as daunomycin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Hepatobiliary excretion of tributylmethylamonium in rats with lipopolysaccharide-induced acute inflammation.

The alteration in the pharmacokinetic behaviors of organic cations (OCs) in rats during acute inflammation (Al) was investigated. Al was induced by an intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) 24 hr prior to the start of pharmacokinetic studies. Tributylmethylammonium (TBuMA) was selected as a model OC since it is largely excreted into bile, and is neither metabolized nor binds to proteins in the body. When TBuMA was administered intravenously to Al rats at a dose of 6.6 micromole/kg, the AUC was increased, while biliary excretion (i.e., cumulative amount and apparent clearance) was decreased compared to normal rats. When TBuMA was administered intravenously to Al rats at a constant rate (i.e., a bolus injection at a dose of 1.5 micromole/kg followed by a constant infusion at a rate of 1.5 micromole/kg/hr for 165 min), steady-state concentrations of plasma and liver concentrations of TBuMA were increased significantly, while in vivo hepatic uptake (amount) and canalicular excretion (clearance) were decreased. These results are consistent with a hypothesis in which both the sinusoidal uptake of TBuMA into hepatocytes via the OCT1 and the canalicular excretion of the compound from hepatocytes via the P-gp are decreased by LPS-induced Al.

Acute Disease↗

PubMed2002

Small intestinal transit does not adequately represent postoperative paralytic ileus in rats.

Small intestinal transit (SIT) has often been regarded as an index of pathophysiological state of postoperative ileus (PI) in rats. The reliability of SIT as an index of PI was examined in the present study. PI was induced via abdominal surgery (i.e., laparotomy with evisceration and manipulation) in rats. For one group of PI-induced rats, SIT of a charcoal test meal was measured. When necessary, the physical state (i.e., severity and site of distension) of the gastrointestinal (GI) tract in each rat was visually examined. For another group of PI-induced rats, abdominal X-ray radiographs were obtained after introducing the barium sulfate suspension. The abdomen was then opened and the physical state of the GI tract was visually examined. The SIT was decreased in most of the PI-induced rats, and the GI distension was observed, with substantial intersubject variations, in all of the PI-induced rats. However, no linear relationship was evident between the SIT and the severity of GI distension (e.g., at 20 h after PI induction). Instead, the severity and site of GI distension could be monitored by the X-ray radiology. Therefore, the use of SIT as an index of Pi should be substantially limited.

Animals↗

PubMed2002

Effect of nitric oxide on the sinusoidal uptake of organic cations and anions by isolated hepatocytes.

The issue of whether or not the presence NOx (NO and oxidized metabolites) in the hepatocytes at pathological levels affects the functional activity of transport systems within the sinusoidal membrane was investigated. For this purpose, the effect of the pretreatment of isolated hepatocytes with sodium nitroprusside (SNP), a spontaneous NO donor, on the sinusoidal uptake of tributylmethylammonium (TBuMA) and triethylmethyl ammonium (TEMA), representative substrates of the organic cation transporter (OCT), and taurocholate, a representative substrate of the Na+/taurocholate cotransporting polypeptide (NTCP), was measured. The uptake of TBuMA and TEMA was not affected by the pretreatment, as demonstrated by the nearly identical kinetic parameters for the uptake (i.e., Vmax, Km and CL(linear)). The uptake of mannitol into hepatocytes was not affected, demonstrating that the membrane integrity remained constant, irregardless of the SNP pretreatment. On the contrary, the uptake of taurocholate was significantly inhibited by the pretreatment, resulting in a significant decrease in Vmax, thus providing a clear demonstration that NOx preferentially affects the function of NTCP rather than OCT on the sinusoidal membrane. A direct interaction between NOx and NTCP or a decrease in Na+/K+ ATPase activity as the result of SNP pretreatment might be responsible for this selective effect of NOx.

Animals↗

PubMed2002

Identification of genes enhanced by protein-calorie malnutrition by differential display polymerase chain reaction (expression of fibrinogen B beta chain, B cell translocation gene 1 and thyroid hormone responsive protein genes).

Protein-calorie malnutrition (PCM), as one of global health problems, arises during protein and/or energy deficit due to disease and nutritional inadequacy. Previously, we showed that PCM elicited oxidative stress with activation of the phase II detoxifying gene expression, which was reversed by cysteine supplementation. As part of the attempts to identify the cellular adaptive responses and the associated gene expression during PCM, the current study was initiated to analyze the genes differentially expressed in the rat during PCM. Among 1,916 bands amplified, 85 putative differentially amplified bands were enhanced by PCM in the liver, while the expression of 64 bands was suppressed. Northern and/or reverse transcription-polymerase chain reaction (RT-PCR) analyses revealed that PCM increased the expression of fibrinogen B beta chain, B cell translocation gene I (BTGI) and thyroid hormone responsive protein (THRP) mRNAs. The increase in the hepatic fibrinogen B beta chain mRNA was not prevented by cysteine supplementation, whereas cysteine decreased the enhancement in the rGSTA2 and microsomal epoxide hydrolase mRNA expression. Cysteine was also active in reversing the increase in BTG1 mRNA during PCM. This was supported by the increase in BTG1 mRNA in H4IIE cells exposed to sulfur amino acid-deprived medium. Northern blot analysis revealed that THRP, highly expressed in the brain in a tissue-specific manner, was induced by PCM and that cysteine supplementation abolished the THRP induction. Conversely, the level of hepatic albumin mRNA was markedly decreased by PCM, which was partially restored by cysteine supplementation. Differential display RT-PCR analysis allowed us to identify the genes that are responsive to oxidative stress during PCM and to characterize the differential role of cysteine on the expression of the fibrinogen B beta chain, BTG1 and THRP genes as a homeostatic adaptive response during protein deficiency.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Characterization of the transport of uracil across Caco-2 and LLC-PK1 cell monolayers.

PURPOSE: The purpose of this study was to characterize the transport of uracil, a pyrimidine nucleobase, in Caco-2 and LLC-PK, cells. METHODS: Caco-2 and LLC-PK1 cells were grown to confluency on a permeable polycarbonate membrane insert to permit transport and uptake experiments after the loading of uracil on either the apical or basolateral side. RESULTS: The vectorial transport of uracil in both directions was saturable with comparable Km and Vmax in Caco-2 cell monolayers, probably because of a Na+-independent transport system located on the basolateral membrane. In LLC-PK1 cell monolayers, two distinct transport systems, namely a Na+-dependent and a Na+-independent, were functional in the apical to basolateral (A-B) transport of uracil. The first system was saturable with a Km value of 3.67 +/- 0.40 microM, a Vmax of 11.31 +/- 0.91 pmol/cm2/min, and a Na+:uracil coupling stoichiometry of 1.28 +/- 0.20. The second system was Na+ independent and satuable with a low affinity (Km, 50.37 +/- 9.61 microM) and Vmax (16.01 +/- 4.48 pmol/cm2/min). The two transport systems appeared to be located on the apical membrane. CONCLUSION: The mechanism of uracil transport differs depending on cell lines; a Na+-independent system on the basolateral membrane in Caco-2 cells and both Na+-dependent and Na+-independent systems on the apical membrane in LLC-PK1 cells seem to be responsible for the difference.

Animals↗

PubMed2002

Mechanism of the reduced elimination clearance of benzylpenicillin from cerebrospinal fluid in rats with intracisternal administration of lipopolysaccharide.

The mechanism responsible for the reduced clearance of benzylpenicillin (BPC) from the cerebrospinal fluid (CSF) was investigated in rats that received an intracisternal administration of lipopolysaccharide (LPS). BPC was intraventricularly injected and its elimination from the CSF studied. During the inflammation created by the LPS administration to the cisterna magna, the clearance of BPC and taurine from the CSF was significantly reduced but reverted to the control level when N-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, was intracisternally administered. The in vitro uptake of BPC and taurine was significantly reduced in the choroid plexus (CP, the blood-CSF barrier) of rats with experimental inflammation and in control CP that had been pretreated with sodium nitroprusside (SNP, an NO donor). Interestingly, the clearance and CP uptake of formycin B, a substrate for a nucleoside transporter, were not affected by the experimental inflammation or by pretreatement with SNP. These observations suggest that the BPC transporter, and probably other transport systems as well, is functionally sensitive to NO in the blood-CSF barrier. Therefore, functional impairment of BPC transport in the CP by NO may be partly responsible for the increase in BPC concentration in the CSF during inflammation such as that caused by meningitis.

Algorithms↗