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  • 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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  • 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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  • 3
    Electronic Resource
    Electronic Resource
    Effect Of Organic Cations On The Renal Tubular Secretion Of Pseudoephedrine In The Rat (2001)
    Melbourne, Australia : Blackwell Science Pty
    Clinical and experimental pharmacology and physiology 28 (2001), S. 0 
    Details
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. Pseudoephedrine is a weak organic base that undergoes renal tubular secretion. The aim of the present study was to assess whether two other commonly used weak organic bases (cimetidine and morphine) inhibit the renal tubular secretion of pseudoephedrine in the rat isolated perfused kidney.2. A total of 12 perfusions were performed with four perfusions in each of three treatment groups. In the control group, pseudoephedrine was administered as a bolus dose of [14C]-pseudoephedrine and unlabelled pseudoephedrine to achieve an initial perfusate concentration of 0.4 μg/mL. For the treatment groups, pseudoephedrine was administered as above and cimetidine or morphine was added to the perfusion medium in increasing concentrations of 0.5–12.5 and 0.2–5.0 μg/mL, respectively.3. The mean (±SD) fraction unbound of pseudoephedrine alone in perfusate was 0.866±0.014 and was not different (P 〉 0.05) in the presence of cimetidine or morphine.4. In control experiments, the renal excretory clearance (CLR) of pseudoephedrine was three-fold greater than glomerular filtration rate (GFR), yielding a ratio consistently greater than unity, which indicates extensive net tubular secretion of pseudoephedrine. The CLR and total clearance of pseudoephedrine were similar, suggesting an absence of renal metabolism of pseudoephedrine.5. The CLR/GFR ratio for pseudoephedrine was not affected by morphine, but was significantly reduced (P 〈 0.05) in the presence of cimetidine.6. The results indicate that cimetidine inhibits the renal tubular secretion of pseudoephedrine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1440-1681.2001.03393.x
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  • 4
    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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  • 5
    Electronic Resource
    Electronic Resource
    Renal excretion mechanisms of the antiviral nucleoside analogue AM 188 IN the rat isolated perfused kidney (2004)
    Oxford, UK : Blackwell Science Pty
    Clinical and experimental pharmacology and physiology 31 (2004), S. 0 
    Details
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. AM 188 is an antiviral guanosine analogue that undergoes extensive renal excretion in humans. The present study was designed to investigate the disposition of AM 188 over a range of concentrations in the rat isolated perfused kidney (IPK) to explore the mechanisms involved in its renal handling.2. Right kidneys of male Sprague-Dawley rats (n = 23) were isolated and perfused in recirculating mode with Krebs'–Henseleit (pH 7.4) buffer containing 0.65% bovine serum albumin, 3.6% dextran, amino acids and glucose. [14C]-Inulin was added to the perfusate reservoir to permit estimation of glomerular filtration rate (GFR). [3H]-AM 188 and unlabelled AM 188 were added to the perfusate as a bolus initially, followed by a constant rate of infusion at 5, 25, 125, 500 or 1000 µg/min to achieve initial target perfusate concentrations of 1, 5, 25, 100 or 200 µg/mL, respectively. During the 130 min over which AM 188 was infused, urine was collected in 10 min intervals (commencing 10 min after the bolus dose) and perfusate was collected at the mid-point of these intervals to permit calculation of the renal clearance (CLR) of AM 188. Binding of AM 188 in perfusate, measured using ultrafiltration, was negligible.3. The bolus dose and infusion regimen produced relatively stable AM 188 concentrations in perfusate in the 5, 25 and 125 µg/min groups and progressively increasing concentrations in the 500 and 1000 µg/min groups. High-pressure liquid chromatography analysis of IPK perfusate and urine suggested that there was no or negligible metabolism of AM 188 in the kidney. The CLR/GFR ratio for AM 188 (mean±SD) was 5.76 ± 1.57, 5.99 ± 0.52, 6.02 ± 1.47, 3.38 ± 0.26 and 1.08 ± 0.42 in the 5, 25, 125, 500 and 1000 µg/min groups, respectively, showing significant reductions at the two highest infusion rates (P 〈 0.05). Although there was no difference between the five groups in the distribution of AM 188 between kidney tissue and perfusate (KT/P), at the end of perfusion the corresponding urine-to-tissue concentration ratio declined significantly in the 1000 µg/min group.4. AM 188 undergoes substantial net renal secretion over a wide range of perfusate concentrations. A reduction in renal clearance at perfusate concentrations above 25 µg/mL could be due to saturation of carrier-mediated transport at the brush border membrane and/or a solubility limitation leading to precipitation of AM 188 in tubular cells and/or tubular urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1440-1681.2004.03946.x
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  • 6
    Electronic Resource
    Electronic Resource
    Application of the axial dispersion model of hepatic drug elimination to the kinetics of diazepam in the isolated perfused rat liver (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 171-193 
    Details
    ISSN: 1573-8744
    Keywords: diazepam ; hepatic elimination ; physiologic models ; dispersion model ; isolated perfused rat liver ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The application of the axial dispersion model to diazepam hepatic elimination was evaluated using data obtained for several conditions using the single-pass isolated perfused rat liver preparation. The influence of alterations in the fraction unbound in perfusate (fu) and perfusate flow (Q) on the availability (F) of diazepam was studied under steady conditions (n=4 in each case). Changes in fu were produced by altering the concentration of human serum albumin (HSA) in the perfusion medium while maintaining diazepam concentration at 1 mg L−1. In the absence of protein (fu = 1), diazepam availability was 0.011 ±0.005 (¯x±SD). 〉As fu decreased, availability progressively increased and at a HSA concentration of 2% (g/100 ml), whenfu was 0.023, diazepam availability was 0.851 ±0.011. Application of the axial dispersion model to the relationship betweenfu andF provided estimates for the dispersion numbe (D N) of 0.337±0.197, and intrinsic clearance (CL int) of 132±34 ml min−1. The availability of diazepam during perfusion with protein-free media was also studied at three different flow rates (15, 22.5, and 30 ml min−1). Diazepam availability always progressively increased as perfusate flow increased, with the axial dispersion model yielding estimates forD N of 0.393 ± 0.128 andCL int of 144 ±38 ml min−1. The transient form of the two-compartment dispersion model was also applied to the output concentration versus time profile of diazepam after bolus input of a radiolabeled tracer into the hepatic portal vein (n=4), providingD N andCL int estimates of 0.251 ±0.093 and 135±59 ml min−1, respectively. Hence, all methods provided similar estimates forD N andCL int. Furthermore, the magnitude of DNis similar to that determined for noneliminated substances such as erythrocytes, albumin, sucrose, and water. These findings suggest that the dispersion of diazepam in the perfused rat liver is determined primarily by the architecture of the hepatic microvasculature.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01071000
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  • 7
    Electronic Resource
    Electronic Resource
    Hepatic Disposition of Fexofenadine: Influence of the Transport Inhibitors Erythromycin and Dibromosulphothalein (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1511-1515 
    Details
    ISSN: 1573-904X
    Keywords: fexofenadine ; hepatic transport ; inhibition ; erythromycin ; dibromosulphothalein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the disposition of fexofenadine in the isolated perfused rat liver and the influence of erythromycin and dibromosulphthalein (DBSP) on the hepatic uptake and biliary excretion of fexofenadine. Methods. Livers from four groups of rats were perfused in a recirculatory manner with fexofenadine HCl added as a bolus (125, 250, 500, or 1000 μg) to perfusate. Livers from another three groups of rats were perfused with 250 μg of fexofenadine HCl. With one group as control, erythromycin (4.0 μg/ml) or DBSP (136 μg/ml) was added to the perfusate of the other groups. In all experiments, perfusate and bile were collected for 60 min; in addition, livers from the second experiment were retained for assay. Fexofenadine was determined in perfusate, bile, and homogenized liver by HPLC. Results. The area under the curve (AUC) of fexofenadine was linearly related to concentration. It was unchanged from control (12,800 ± 200 ng·h/ml) by erythromycin (14,400 ± 2000 ng·h/ml), but was increased 95% by DBSP (25,000 ± 2600 ng·h/ml, P 〈0.001). The ratios of the concentrations of fexofenadine in liver/perfusate were decreased significantly by DBSP; those for bile/liver were increased by erythromycin. Conclusions. Erythromycin reduced the canalicular transport of fexofenadine into bile, whereas DBSP reduced uptake across the sinusoidal membrane.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007609225851
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  • 8
    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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