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  • 1995-1999  (4)
  • 1
    Electronic Resource
    Electronic Resource
    EFFECTS OF ALBUMIN ON THE DISPOSITION OF MORPHINE AND MORPHINE-3-GLUCURONIDE IN THE RAT ISOLATED PERFUSED LIVER (1997)
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 24 (1997), S. 0 
    Details
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The effect of albumin on the disposition of morphine and hepatically generated morphine-3-glucuronide (M3G) was investigated in the single-pass rat isolated perfused liver.1. Interest in the pharmacokinetic and pharmacodynamic properties of the enantiomers of chiral drugs has greatly increased in recent years. This is particularly so for agents used in anaesthesia.2. Chiral compounds are those that can exist in two non-superimposable forms. Each form is termed an enantiomer or stereoisomer. Two naming systems are in use: one uses the terms (+) and (–) to indicate the direction the compound will rotate polarized light, while the other system, based on the absolute three-dimensional structure of the enantiomers, uses the terms R and S.3. Investigation of the stereoisomers of the volatile anaesthetic agent isoflurane is increasing our understanding of the mechanism of general anaesthesia. Current evidence suggests a protein, rather than a lipid, receptor site.4. Investigation of the stereoisomers of local anaesthetics is increasing the safety of these drugs.5. For bupivacaine, a widely used amide local anaesthetic, important enantiomeric differences can be found for toxicity, clinical effect and pharmacokinetics. In particular S-(–)-bupivacaine has an improved central nervous system and cardiac safety profile. This is partly explained by the pharmacokinetic differences.6. Based on these differences, ropivacaine, a propyl homo-logue of bupivacaine, has been produced solely as the S-(–)-enantiomer. The available evidence suggests significantly improved safety for this agent over racemic bupivacaine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1440-1681.1997.tb01797.x
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    MEMBRANE TRANSPORT AS A DETERMINANT OF THE HEPATIC ELIMINATION OF DRUGS AND METABOLITES (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 23 (1996), S. 0 
    Details
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The liver is ideally suited for the efficient uptake of drugs from sinusoidal blood. For most drugs, uptake into hepatocytes across the basolateral membrane occurs via passive diffusion, with minimal relaiance on carrier-mediated transport systems. Often, this passive diffusion is so efficient that uptake is ratelimited by the delivery of the drug to the lvier (i.e. blood flow) rather than membrane transport per se2. For highly polar molecules, passive diffusion no longer represents an efficient mode of hepatocellular uptake and there is an increased reliance on carrier-mediated transport systems. For these compounds, membrane transport may dictate the overall efficiency of hepatic elimination.3. Drug metabolites, particularly conjugated metabolites, such as sulphates and glucuronides, are invariably more polar than their precursors and are more likely to experience hepatocyte membranes as diffusional barriers. In the presence of such a barrier, the hepatocellular disposal of a locally formed metabolite will depend critically on the presence and activity of carrier-mediated transport systems for sinusoidal efflux and biliary excretion. Transporters of current interest include P-glycoproteins, which are responsible for the biliary excretion of a rage of organic cations, and the canalicular multispecific organic anion transporter.4. Intracellular trapping of hepatically formed metabolites, secondary to low membrane permeability, is clinically important as many metabolites are potentially hepatotoxic and/or capable of interfering with the hepatic transport of endogenous compounds or other durgs and metabolites. In addition, if the metabolite is unstable, intracellular accumulation can lead to the regeneration of the precursor and ‘futile cycling’ within hepatocytes.5. An increased understanding of the factors influencing the intracellular concentrations of drugs and hepatically formed metabolites in the lvier will improve our ability to specifically treat liver disorders, such as hepatocellular carcinoma and malaria, and minimize the risk of hepatotoxicity from drugs and other xenobiotics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1440-1681.1996.tb01151.x
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    EFFECT OF CATIONIC DRUGS ON THE RENAL SECRETION OF RANITIDINE IN THE RAT ISOLATED PERFUSED KIDNEY (1998)
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 25 (1998), S. 0 
    Details
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The rat isolated perfused kidney (IPK) was used to determine whether the renal tubular secretion of ranitidine is influenced by clinically relevant concentrations of other organic cationic drugs (amantadine, pseudoephedrine, triamterene and trimethoprim) that also undergo tubular secretion.2. Ranitidine and [3H]-ranitidine were administered to the recirculating perfusion medium as a loading dose followed by a constant infusion to maintain clinically relevant perfusate ranitidine concentrations in the range 400–700 ng/mL. The renal clearance of ranitidine (CLR) was calculated, as was glomerular filtration rate (GFR), from the renal clearance of [14C]-inulin.3. A total of 20 perfusions were performed and, in each case, ranitidine was administered for 80 min. In four control IPK, no drug other than ranitidine was administered. In the remaining IPK, amantadine, pseudoephedrine, triamterene or trimethoprim (n= 4 in each case) were administered to achieve low, medium and high concentrations during the 20–40, 40–60 and 60–80 min periods, respectively.4. The mean (± SD) unbound fraction of ranitidine in the perfusion medium was 0.889±0.046 and was not altered (P〉0.05) by the presence of the other drugs.5. The CLR/GFR ratio for ranitidine in all kidneys was substantially greater than unity and had a mean value of 10.65 or greater in control kidneys, indicating extensive net tubular secretion.6. The CLR/GFR was not affected (P〉0.05) by amantadine, pseudoephedrine or triamterene at any concentration or by trimethoprim at the low concentration. However, medium (2000 ng/mL) and high (5000 ng/mL) concentrations of trimethoprim caused significant reductions in CLR/GFR of 20 and 28%, respectively (P〈0.05).7. The results indicate that at clinically relevant concentrations the renal tubular secretion of ranitidine is inhibited by trimethoprim, but not by amantadine, pseudoephedrine or triamterene.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1440-1681.1998.tb02140.x
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Comparison of the Disposition of Hepatically-Generated Morphine-3-glucuronide and Morphine-6-glucuronide in Isolated Perfused Liver from the Guinea Pig (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1014-1018 
    Details
    ISSN: 1573-904X
    Keywords: morphine ; morphine-3-glucuronide ; morphine-6-glucuronide ; liver ; membrane transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Humans and guinea pigs metabolise morphine extensively, forming the isomers morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs. Methods. Livers were perfused at 30 ml/min in a non-recirculating manner with Krebs bicarbonate buffer containing morphine (6 to 7 μM). Perfusing medium, venous perfusate and bile were collected at regular intervals and concentrations of morphine, M3G and M6G determined by reversed-phase HPLC. Results. Concentrations of morphine, M3G and M6G in perfusate and the rates of biliary excretion of M3G and M6G were consistent between 20 and 50 min of perfusion. The mean (±s.d.) ratio for the rate of formation of M3G relative to M6G was 3.7 ± 1.5. A mean 33 ± 3% of morphine extracted by the liver was recovered as summed M3G and M6G. Of the M3G and M6G formed during a single passage, 19 ± 11% and 9 ± 9%, respectively, was excreted into bile; the values were significantly different (P = 0.002). Conclusions. A greater fraction of hepatically-generated M3G excreted into bile compared to that for M6G reflects differences in their relative transport across sinusoidal and canalicular membranes of hepatocytes, possibly via carrier-mediated systems.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012145126847
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    Paper (German National Licenses)
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