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  • 1
    Electronic Resource
    Electronic Resource
    A fluorescent probe and a photoaffinity labeling reagent to study the binding site of maytansine and rhizoxin on tubulin (1993)
    s.l. : American Chemical Society
    Bioconjugate chemistry 4 (1993), S. 284-289 
    Details
    ISSN: 1520-4812
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/bc00022a006
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  • 2
    Electronic Resource
    Electronic Resource
    Catalytic cooperativity and subunit interactions in E. coli glutamine synthetase binding and kinetics with methionine sulfoximine and related inhibitors (1982)
    s.l. : American Chemical Society
    Biochemistry 21 (1982), S. 2168-2177 
    Details
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/bi00538a028
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  • 3
    Electronic Resource
    Electronic Resource
    EVALUATION OF DRUG-DRUG INTERACTION IN THE HEPATOBILIARY AND RENAL TRANSPORT OF DRUGS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 689-723 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Recent studies have revealed the import role played by transporters in the renal and hepatobiliary excretion of many drugs. These transporters exhibit a broad substrate specificity with a degree of overlap, suggesting the possibility of transporter-mediated drug-drug interactions with other substrates. This review is an overview of the roles of transporters and the possibility of transporter-mediated drug-drug interactions. Among the large number of transporters, we compare the Ki values of inhibitors for organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs) and their therapeutic unbound concentrations. Among them, cephalosporins and probenecid have the potential to produce clinically relevant OAT-mediated drug-drug interactions, whereas cyclosporin A and rifampicin may trigger OATP-mediated ones. These drugs have been reported to cause drug-drug interactions in vivo with OATs or OATP substrates, suggesting the possibility of transporter-mediated drug-drug interactions. To avoid adverse consequences of such transporter-mediated drug-drug interactions, we need to be more aware of the role played by drug transporters as well as those caused by drug metabolizing enzymes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121444
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  • 4
    Electronic Resource
    Electronic Resource
    Acid-catalyzed reaction of ethyl cyanoformate with aromatic amines in acetic acid: facile synthesis of N-substituted amidinoformic acids and ethyl 4-quinazolone-2-carboxylate (1978)
    s.l. : American Chemical Society
    The @journal of organic chemistry 43 (1978), S. 4485-4487 
    Details
    ISSN: 1520-6904
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/jo00417a020
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  • 5
    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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  • 6
    Electronic Resource
    Electronic Resource
    Prediction of ACNU plasma concentration-time profiles in humans by animal scale-up (1990)
    Springer
    Cancer chemotherapy and pharmacology 27 (1990), S. 20-26 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Plasma concentration-time profiles of nimustine hydrochloride, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), in the mouse, rat, rabbit, and dog were determined by high-performance liquid chromatographic analysis. The pharmacokinetic parameters for these four animal species and previously reported clinical data were analyzed for investigation of interspecies correlation. Loglog plots of body weight (W; kg) vs total plasma clearance (CLtot, p; ml/min) and steady-state distribution volume (Vd, ss; 1) for the four animal species were linear, with high correlation coefficients (r 0.996 for both parameters), despite the fact that the nonrenal clearance was 〉97% in these species. Linear regression on the plots excluding human data yielded allometric equations (CLtot,p=50.6 W0.957; Bd, ss=1.29 W1.03) that were extrapolated to predict ACNU pharmacokinetic parameters in humans. For both parameters, however, there were 3-fold differences between the predicted and observed parametric values. To investigate these discrepancies, we measured serum protein binding of ACNU in these animal species and in humans. The values of CLtot,p and Vd,ss were converted into those of CLu tot,p and Vd,u ss, which correspond to the parameters for unbound ACNU. In this case, correlation coefficients of the log-log plots excluding human data (CLu tot,p=71.7 W0.891; Bd,u ss=1.82 W0.966) were also high (r≥0.991). The extrapolated values vs those observed in a 70-kg human were the following: CLu tot,p, 3,160 vs 2,290 ml/min; Vd,u ss, 110 vs 1061. Thus, the animal data were successfully extrapolated to yield better predictions of human pharmacokinetic parameters if the analysis was based on the unbound plasma concentration of ACNU. In addition, the predicted plasma concentration-time profile for humans also showed good agreement with the observed ones. These results suggest the importance of measuring unbound fractions of drugs for more accurate prediction of human pharmacokinetic parameters by extrapolation of animal data to the human situation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689271
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  • 7
    Electronic Resource
    Electronic Resource
    Multiplicity of biliary excretion mechanisms for the camptothecin derivative irinotecan (CPT-11), its metabolite SN-38, and its glucuronide: role of canalicular multispecific organic anion transporter and P-glycoprotein (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. S44 
    Details
    ISSN: 1432-0843
    Keywords: Key words Irinotecan ; Biliary excretion ; P-glycoprotein ; cMOAT
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A frequent dose-limiting effect of irinotecan (CPT-11) is its gastrointestinal toxicity (diarrhea), which is thought to be related to biliary excretion of CPT-11 and its metabolites. Accordingly, we have investigated the mechanism of biliary excretion of these compounds. In vivo pharmacokinetic studies revealed that the biliary excretion of the four anionic forms of CPT-11 and its metabolites was reduced in Eisai hyperbilirubinemic rats, which carry a mutation of the hepatic canalicular multispecific organic anion transporter (cMOAT) gene. The protein encoded by this gene is expressed on the bile canalicular membrane and is responsible for the transport of organic anions into bile. Detailed analysis using isolated liver bile canalicular membrane vesicles to identify transport systems showed that cMOAT is responsible for biliary excretion of the low-affinity component of the carboxylate form of CPT-11 and the high-affinity component of both the lactone and carboxylate forms of SN-38 glucuronide. The carboxylate form of SN-38 is transported by cMOAT alone. Transport of the high-affinity component of CPT-11 was inhibited by verapamil and PSC-833, but their effect on the transport of its low-affinity component was minimal. In addition, ATP dependence in the uptake of CPT-11 by membrane vesicles obtained from a P-glycoprotein (P-gp)-overexpressing cell line was observed. Thus P-gp may be responsible for transport of the high-affinity component of the carboxylate form of CPT-11.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800051078
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  • 8
    Electronic Resource
    Electronic Resource
    Cell killing action of cell cycle phase-non-specific antitumor agents is dependent on concentration-time product (1988)
    Springer
    Cancer chemotherapy and pharmacology 21 (1988), S. 185-190 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Based on a pharmacokinetic model proposed by Jusko, which assumes that the cell killing action of cell cycle phase-non-specific agents occurs as a bimolecular reaction depending on drug concentration and cell density, we derived a cell kill kinetic equation for these drugs, including the decomposition constant in culture medium. This equation revealed that the cell killing activity of these drugs depends on the value of concentration x exposure time or the area under the drug concentration-time curve (AUC). It was also clarified that the curves for concentration-exposure time necessary for 90% cell kill on a log scale simulated on the basis of the equation differ according as whether drugs are stable or unstable in the culture medium, being expected to be linear with a slope of-1 in the former case, and to take the form of an asymptotic curve in the latter. For three cell cycle phase-non-specific agents, mitomycin C (MMC), 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)3-nitrosourea hydrochloride (ACNU), and nitrogen mustard (HN2), we assessed the concentrations necessary for 90% cell kill (IC90) with various exposure times and the degradation rate constants under the culture conditions used. MMC was quite stable during the incubation, while ACNU and HN2 were unstable. When IC90's and exposure times were plotted on the above-mentioned graph, a linear relationship with a slope of-1 was seen for MMC, while for ACNU and HN2 the anticipated asymptotic curves resulted. We also ascertained that the decomposition constants for ACNU and HN2 expected on the basis of these curves showed a good agreement with the corresponding experimentally observed values. These results indicate that the cell killing action of cell cycle phase-non-specific drugs can be well described by a pharmacodynamic model and equation employing their decomposition constants and are dependent on the concentration-time product.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00262767
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of CPT-11 in rhesus monkeys (1997)
    Springer
    Cancer chemotherapy and pharmacology 41 (1997), S. 103-108 
    Details
    ISSN: 1432-0843
    Keywords: Key words CPT-11 ; Pharmacokinetics ; Monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To examine the pharmacokinetic relationships between humans and monkeys, we studied the disposition of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), in rhesus monkeys. Methods: CPT-11 was administered to a total of six monkeys at doses of 3, 7, 15 and 25 mg/kg by intravenous infusion for 10 min and plasma concentrations and pharmacokinetic parameters of CPT-11 determined. Results: Maximum plasma concentrations at 25 mg/kg reached around 10 000 ng/ml, and dropped to 500 ng/ml in 8 h. Plasma concentrations of SN-38 remained between 2 and 10 ng/ml. Mean values of systemic clearance, mean residence time and distribution volume at steady state, the major pharmacokinetic parameters for CPT-11, were 13.3 (ml/min per kg), 192 (min) and 2553 (ml/kg), respectively. The initial plasma concentration ratio of lactone to total CPT-11, 76%, declined to about 20% within 75 min, and the final ratio was about 40% at 8 h; the initial ratio of SN-38 was 72%, dropped to 34% within 70 min and finally recovered to 55% at 8 h. Conclusion: Comparison with human data revealed that systemic clearances of CPT-11 and the maximum AUC of SN-38 were not as different between humans and monkeys as between humans and mice, but the metabolic conversion of CPT-11 into SN-38 in monkeys was significantly lower than in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050715
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  • 10
    Electronic Resource
    Electronic Resource
    Determination of the Rate-Limiting Step in the Hepatic Elimination of YM796 by Isolated Rat Hepatocytes (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 110-116 
    Details
    ISSN: 1573-904X
    Keywords: clearance ; efflux ; hepatocytes ; influx ; membrane permeability ; metabolism ; rate-limiting step
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The membrane permeability clearance and intrinsic metabolic clearance of a drug in the liver were estimated using isolated rat hepatocytes, and the rate-limiting step in the overall intrinsic clearance of the drug in vivo was investigated. For this purpose, an anti-dementia drug, (S)-(-)-2,8-dimethyl-3-methylene-l-oxa-8-azaspiro [4,5] de-cane-L-tartarate monohydrate (YM796) was used as a model drug. Methods. The parent drug and its metabolites in both medium and cells were separated by thin-layer chromatography (TLC). The total amount of drug taken up by hepatocytes and the total amount of metabolites were plotted against the AUC of YM796 in the medium or cells to obtain the kinetic parameters. Results. While the influx clearance (PSint) through the sinusoidal membrane defined in terms of YM796 concentration in the medium was almost constant, irrespective of the concentration of YM796 in the medium, the intrinsic metabolic clearance (CLint) and the efflux clearance (PSeff) defined in terms of the total concentration of YM796 in the cells markedly decreased and increased, respectively, as the concentration of YM796 increased. The overall intrinsic metabolic clearance (Clint,all), defined in terms of the YM796 concentration in the medium, corresponding to the hepatic intrinsic clearance obtained from thein vivo pharmacokinetic data on the drug, was comparable with PSinf at low concentrations of YM796. As the YM796 concentration increased, however, Clint,all fell markedly approaching CLint. Conclusions. While, at low concentrations of YM796, CLint,all was predominantly affected by membrane permeability clearance, at high concentrations it was completely rate-determined by the intrinsic metabolic clearance because of the marked reduction in CLint resulting from the saturation of YM796 metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018883115189
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