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  • 1
    Electronic Resource
    Electronic Resource
    Efflux of a suppressive neurotransmitter, GABA, across the blood–brain barrier (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 79 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In this study, GABA efflux transport from brain to blood was estimated by using the brain efflux index (BEI) method. [3H]GABA microinjected into partietal cortex area 2 (Par2) of the rat brain was eliminated from the brain with an apparent elimination half-life of 16.9 min. The blood–brain barrier (BBB) efflux clearance of [3H]GABA was at least 0.153 mL/min/g brain, which was calculated from the elimination rate constant (7.14 × 10−2 min−1) and the distribution volume in the brain (2.14 mL/g brain). Direct comparison of the apparent BBB influx clearance [3H]GABA (9.29 µL/min/g brain) and the apparent efflux clearance (153 µL/min/g brain) indicated that the efflux clearance was at least 16-fold greater than the influx clearance. In order to reduce the effect of metabolism in the neuronal cells following intracerebral microinjection, we determined the apparent efflux of [3H]GABA in the presence of nipecotic acid, a GABA transport inhibitor in parenchymal cells, using the BEI method. Under such conditions, the elimination of [3H]GABA across the BBB showed saturation and inhibition by probenecid in the presence of nipecotic acid. Furthermore, the uptake of [3H]GABA by MBEC4 cells was inhibited by GABA, taurine, β-alanine and nipecotic acid in a concentration-dependent manner. It is likely that GABA inhibits the first step in the abluminal membrane uptake by brain endothelial cells, and that probenecid selectively inhibits the luminal membrane efflux transport process from the brain capillary endothelial cells based on the in vivo and in vitro evidence. The BBB acts as the efflux pump for GABA to reduce the brain interstitial fluid concentration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00540.x
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  • 2
    Electronic Resource
    Electronic Resource
    Physiological Modeling of Altered Pharmacokinetics of a Novel Anticancer Drug, UCN-01 (7-Hydroxystaurosporine), Caused by Slow Dissociation of UCN-01 from Human α1-Acid Glycoprotein (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 553-564 
    Details
    ISSN: 1573-904X
    Keywords: α1-acid glycoprotein ; protein binding ; dissociation rate ; species difference ; physiological model ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The extremely low clearance and small distribution volumeof UCN-01 in humans could be partly due to the high degree of bindingto hAGP (1,2). The quantitative effects of hAGP on the pharmacokineticsof UCN-01 at several levels of hAGP and UCN-01 were estimatedin rats given an infusion of hAGP to mimic the clinical situation anda physiological model for analysis was developed. Methods. The plasma concentrations of UCN-01 (72.5–7250 nmol/kgiv) in rats given an infusion of hAGP, 15 or 150 nmol/h/kg, weremeasured by HPLC. Pharmacokinetic analysis under conditionsassuming rapid equilibrium of protein binding and incorporating thedissociation rate was conducted. Results. The Vdss and CLtot of UCN-01 (725 nmol/kg iv) in ratsgiven an infusion of hAGP, 150 nmol/h/kg, fell to about 1/250 and 1/700that in control rats. The Vdss and CLtot following 72.5–7250nmol/kg UCN-01 to rats given 150 nmol/h/kg hAGP were 63.9–688ml/kg and 3.18–32.9 ml/h/kg, respectively, indicating non-linearitydue to saturation of UCN-01 binding. The CLtot estimated by thephysiological model assuming rapid equilibrium of UCN-01 bindingto hAGP, was six times higher than the observed value while the CLtotestimated by the model incorporating koff, measured using DCC, wascomparable with the observed value. Conclusions. These results suggest that the slow dissociation ofUCN-01 from hAGP limits its disposition and elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007512832006
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  • 3
    Electronic Resource
    Electronic Resource
    Detection of the Membrane Protein Recognized by the Kidney-Specific Alkylglucoside Vector (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 49-54 
    Details
    ISSN: 1573-904X
    Keywords: kidney ; sugar ; glucoside ; cross-linking ; membrane protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Previously, we suggested that alkylglucoside can be aneffective vector for renal-specific drug delivery (Suzuki et al., J. Pharmacol.Exp. Ther., 288:57–61, 1999). The purpose of the present study is tocharacterize the membrane protein which is recognized by thisalkylglucoside. Methods. The binding of [125I] tyrosine conjugated with aoctylthioglucoside (Glc-S-C8-[125I]Tyr) Glc-S-C8-[125I]Tyr to crude membranefractions of kidney was determined. In addition, the membrane wascross-linked with this alkylglucoside and examined by sodium dodecylsulfate-polyacrylamide gel electrophoresis. Results. Glc-S-C8-[125I]Tyr was shown to have a specific binding siteon the kidney membrane (Kd = 931 nM and Bmax = 987pmol/mg protein). Cross-linking of the membrane with Glc-S-C8-[125I]Tyrresulted in the detection of a protein (Mr = 62,000), which wasunaffected by reducing agents. The results of this cross-linking study wereconsistent with previous information on its localization and bindingcharacteristics. Conclusions. The kidney membrane protein, to which alkylglucosidebinds in a specific manner, has a molecular weight of 62,000.Cross-linking is a useful tool for detecting this novel membrane proteinin kidney.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007566408323
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  • 4
    Electronic Resource
    Electronic Resource
    Quantitative Prediction of In Vivo Drug-Drug Interactions from In Vitro Data Based on Physiological Pharmacokinetics: Use of Maximum Unbound Concentration of Inhibitor at the Inlet to the Liver (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 336-343 
    Details
    ISSN: 1573-904X
    Keywords: drug interaction ; prediction ; physiologically-based pharmacokinetics ; tolbutamide ; sulfaphenazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To assess the degree to which the maximum unboundconcentration of inhibitor at the inlet to the liver (Iinlet,u,max), used in theprediction of drug-drug interactions, overestimates the unboundconcentration in the liver. Methods. The estimated value of Iinlet,u,max was compared with theunbound concentrations in systemic blood, liver, and inlet to the liver,obtained in a simulation study based on a physiological flow model.As an example, a tolbutamide/sulfaphenazole interaction was predictedtaking the plasma concentration profile of the inhibitor intoconsideration. Results. The value of Iinlet,u,max differed from the concentration in eachcompartment, depending on the intrinsic metabolic clearance in theliver, first-order absorption rate constant, non-hepatia clearance andliver-to-blood concentration ratio (Kp) of the inhibitor. The AUC oftolbutamide was predicted to increase 4-fold when co-administeredwith sulfaphenazole, which agreed well with in vivo observations andwas comparable with the predictions based on a fixed value of Iinlet,u,max.The blood concentration of tolbutamide was predicted to increase whenit was co-administered with as little as 1/100 of the clinical doseof sulfaphenazole. Conclusions. Although Iinlet,u,max overestimated the unboundconcentration in the liver, the tolbutamide/sulfaphenazole interaction couldbe successfully predicted by using a fixed value of Iinlet,u,max, indicatingthat the unbound concentration of sulfaphenazole in the liver after itsclinical dose is by far larger than the concentration to inhibitCYP2C9-mediated metabolism and that care should be taken when it isco-administered with drugs that are substrates of CYP2C9.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007509324428
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  • 5
    Electronic Resource
    Electronic Resource
    Prediction of In Vivo Interaction Between Triazolam and Erythromycin Based on In Vitro Studies Using Human Liver Microsomes and Recombinant Human CYP3A4 (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 419-426 
    Details
    ISSN: 1573-904X
    Keywords: drug interaction ; mechanism-based inhibition ; triazolam ; erythromycin ; physiologically-based pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To quantitatively predict the in vivo interaction betweentriazolam and erythromycin, which involves mechanism-basedinhibition of CYP3A4, from in vitro studies using human liver microsomes(HLM) and recombinant human CYP3A4 (REC). Methods. HLM or REC was preincubated with erythromycin in thepresence of NADPH and then triazolam was added. α- and 4-hydroxy(OH) triazolam were quantified after a 3 min incubation and the kineticparameters for enzyme inactivation (kinact and K′ app) were obtained.Drug-drug interaction in vivo was predicted based on aphysiologically-based pharmacokinetic (PBPK) model, using triazolam anderythromycin pharmacokinetic parameters obtained from the literature and kineticparameters for the enzyme inactivation obtained in the in vitro studies. Results. Whichever enzyme was used, triazolam metabolism was notinhibited without preincubation, even if the erythromycin concentrationwas increased. The degree of inhibition depended on preincubationtime and erythromycin concentration. The values obtained for kinactand K′ app were 0.062 min−1 and 15.9 μM (α-OH, HLM), 0.055 min−1and 17.4 μM (4-OH, HLM), 0.173 min−1 and 19.1 μM (α-OH, REC),and 0.097 min−1 and 18.9 μM (4-OH, REC). Based on the kineticparameters obtained using HLM and REC, the AUCpo of triazolamwas predicted to increase 2.0- and 2.6-fold, respectively, followingoral administration of erythromycin (333 mg t.i.d. for 3 days), whichagreed well with the reported data. Conclusions. In vivo interaction between triazolam and erythromycinwas successfully predicted from in vitro data based on a PBPK modelinvolving a mechanism-based inhibition of CYP3A4.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007572803027
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Study of the Hepatobiliary Transport of Indomethacin (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 432-438 
    Details
    ISSN: 1573-904X
    Keywords: indomethacin ; hepatic uptake ; Ntcp ; oatp ; biliary excretion ; cMOAT/MRP2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The biliary excreted amount of indomethacin and itsglucuronide is related to the intestinal toxicity of this drug. In the presentstudy, we investigated the hepatobiliary transport of indomethacin.Methods. The uptake of indomethacin into primary cultured rathepatocytes and COS-7 cells transfected with cDNA encoding sodiumtauro-cholate co-transporting polypeptide or organic anion transportingpolypeptide 1 was examined. Moreover, we compared the biliaryexcretion of indomethacin and its glucuronide between Sprague-Dawley(SD) rats and Eisai hyperbilirubinemic rats (EHBR) whose canalicularmultispecific organic anion transporter/multidrug resistance associatedprotein 2 (cMOAT/MRP2) function is hereditarily defective.Results. The uptake of indomethacin into rat hepatocytes was mediatedby Na+-dependent and independent active transport systems. Neithertransfectant stimulated the uptake of indomethacin. After intravenousinfusion of indomethacin to SD rats, the biliary excretion ofindomethacin glucuronide exceeded that of indomethacin. The indomethacintransport clearance across the bile canalicular membrane wascomparable between SD rats and EHBR, whereas the corresponding value forindomethacin glucuronide in EHBR was approximately 50% that inSD rats.Conclusions. These results indicate that another transporter(s) isinvolved in the hepatic uptake of indomethacin and the canaliculartransport of indomethacin glucuronide is mediated by cMOAT/MRP2whereas that of indomethacin is not mediated by cMOAT/MRP2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007576903935
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  • 7
    Electronic Resource
    Electronic Resource
    Biliary Excretion of 17β-Estradiol 17β-d-Glucuronide Is Predominantly Mediated by cMOAT/MRP2 (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 546-552 
    Details
    ISSN: 1573-904X
    Keywords: cMOAT/MRP2 ; biliary excretion ; 17β-estradiol 17β-d-glucuronide ; P-glycoprotein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The mechanism for the biliary excretion of 17β-estradiol17β0-d-glucuronide (E217βG), a cholestatic metabolite of estradiol, isstill controversial. The purpose of the present study is to examine thetransport of E217βG across the bile canalicular membrane. Methods. We examined the uptake of [3H]E217βG by isolatedcanalicular membrane vesicles (CMVs) prepared from Sprague-Dawley (SD)rats and Eisai Hyperbilirubinemic rats (EHBR) whose canalicularmultispecific organic anion transporter/multidrug resistance associatedprotein 2 (cMOAT/MRP2) function is hereditarily defective. Also,in vivo biliary excretion of intravenously administered [3H]E217βGwas examined. Results. In CMVs prepared from SD rats, but not from EHBR, amarked ATP-dependent uptake of [3H]E217βG was observed.Moreover, E217βG competitively inhibited the ATP-dependent uptake of[3H]2,4-dinitrophenyl-S-glutathione (DNP-SG). In addition, nosignificant inhibitory effect of verapamil (100 μM) and PSC-833 (5 μM) onthe uptake of [3H]E217βG was observed. In vivo, the biliary excretionof intravenously administered [3H]E217βG was severely impaired inEHBR while the biliary excretion of [3H]E217βG in SD rats wasreduced by administering a cholestatic dose (10 μmol/kg) unlabeledE217βG, but not by PSC-833 (3 mg/kg). Conclusions. The transport of E217βG across the bile canalicularmembrane is predominantly mediated by cMOAT/MRP2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026412915168
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