Isolated perfused rat liver

To further investigate the role of the liver in brevetoxin metabolism, PbTx-3 was studied in the isolated perfused rat liver model (27, 28). Radiolabeled PbTx-3 was added to the reservoir of a recirculating system and allowed to mix thoroughly with the perfusate. Steady-state conditions were reached within 20 min. At steady-state, 55-65% of the delivered PbTx-3 was metabolized and/or extracted by the liver 26% remained in the effluent perfusate. Under a constant liver perfusion rate of 4 ml/min, the measured clearance rate was 0.11 ml/min/g liver. The calculated extraction ratio of 0.55 was in excellent agreement with the in vivo data. Radioactivity in the bile accounted for 7% of the total radiolabel perfused through the liver. PbTx-3 was metabolized and eliminated into bile as parent toxin plus four more-polar metabolites (Figure 3). Preliminary results of samples stained with 4-(p-nitrobenzyl)-pyridine (29) indicated the most polar metabolite was an epoxide. 

Bonse G, Urban T, Reichert D, et al. 1975. Chemical reactivity, metabolic oxirane formation, and biological reactivity of chlorinated ethylenes in the isolated perfused rat liver preparation. Biochem Pharmacol 24 1829-1834. 

Younes, M. and Strubelt, O. (1990). The role of iron and glutathione in t-butyl hydroperoxide-induced damage towards isolated perfused rat livers. J. Appl. Toxicol. 10, 319-324. 

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. 

Ward et al. [130] studied the pharmacokinetics of (+)- and (—)-primaquine in the isolated perfused rat liver preparation. The perfusate plasma concentrations of primaquine in the isolated, perfused rat liver, declined biexponentially following the addition of either (+)- or (—)-primaquine at doses 0.5-2.5 mg in the perfusate reservoir. There were no differences between pharmacokinetic profiles of the two isomers at the 0.5 mg dose. By contrast, the elimination of (—)-primaquine was greater than (+)-primaquine when either was added in a dose of 2.5 mg also, the clearance of the (—)-isomer was greater, the half-life was shorter, and the area under the plasma concentration curve was shorter. The volume of distribution was similar for the two isomers. These results are relevant to both the therapeutic efficacy and toxicity of primaquine. 

Younes, M. and O. Strubelt. 1988. Cyanide-induced injury to the isolated perfused rat liver. Pharmacol. Toxicol. 63 382-385. 

Needleman, P., Harkey. A. B., Role of endogenous glutathione in the metabolism of glyceryl trinitrate by isolated perfused rat liver. Biochem. Pharmacol. 20 (1971), p. 1867-1876... 

KlevayLM. 1971. Endrin excretion by the isolated perfused rat liver A sexual difference (35385) Department of Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, OH. 

Strugala GJ, Elbers R. 1984. Metabolism of amygdalin and prunasin in the isolated perfused rat liver. Naunyn-Schmiedeberg s Archives of Pharmacology. 325(Suppl.) R23. 

Agarwal AK, Mehendale HM. 1986. Effect of chlordecone on carbon tetrachloride-induced increase in calcium uptake in isolated perfused rat liver. Toxicol Appl Pharmacol 83 342-348. Cited in text... 

Desaiah D, Ho IK, Mehendale HM. 1977b. Inhibition of mitochondrial Mg2+-ATPase activity in isolated perfused rat liver by Kepone. Biochem Pharmacol 26 1155-1159. 

Teo S Vore M. 1991. Mirex inhibits bile acid secretory function in vivo and in the isolated perfused rat liver. Toxicol Appl Pharmacol 109(1) 161-170. 

Ballinger LN, Cross SE, Roberts MS. 1995. Availability and mean transit times of phenol and its metabolites in the isolated perfused rat liver Normal and retrograde studies using tracer concentrations of phenol. J Pharm Pharmacol 47 949-956. 

M. Wang, R. G. Dickinson, Disposition and Covalent Binding of Diflunisal and Diflunisal Acyl Glucuronide in the Isolated Perfused Rat Liver , Drug Metab. Dispos. 1998, 26, 98 - 104. 

Rannug U, Beije B. 1979. The mutagenic effect of 1,2-dichloroethane on Salmonella typhimurium. Part II. Activation by the isolated perfused rat liver. Chem-Biol Interact 24 265-286. 

Sugiyama and Kato [63] described a model for the receptor-mediated endocytosis of the polypeptide hormones epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in isolated perfused rat liver and in isolated rat hepatocytes, to estimate the efficiency of dmg targeting using these polypeptide hormones as potential drng carriers. 

Koob M, Dekant W. 1992. Biotransformation of the hexachlorobutadiene metabolites 1-(glutathion-S -yl)-pentachlorobutadiene and 1-(cystein-S-yl)-pentachlorobutadiene in the isolated perfused rat liver. Xenobiotica 22 125-138. 

Bitzenhofer, U.N., Kessler, W., Kreuzer, PE. Filser, J.G. (1994) Kinetics of styrene and its metabolite st rene-7,8-oxide in the isolated perfused rat liver (Abstract No. 390). The Toxicologist, 14. 118... 

Dimethylhydrazine is metabolized by a sequence of oxidation steps, first dehydrogenation to azomethane, A -oxidation of this to azoxymethane and finally a C-oxidation to methylazoxymethanol (Fiala, 1975, 1977). This last metabolite decomposes to give the highly reactive methyldiazonium ion to which the carcinogenicity of the compound has been attributed. The sequential nature of these oxidation steps has been shown in the isolated perfused rat liver (Wolter Frank, 1982). Fiala (1977) showed that the C-oxidation of azoxymethane to methylazoxymethanol is catalysed by hepatic microsomes, while Schoental (1973) found that methylazoxymethanol was converted to the corresponding aldehyde by an NAD-dependent dehydrogenase. 

Wolter, S. Frank, N. (1982) Metabolism of 1,2-dimethylhydrazine in isolated perfused rat liver. Chem.-biol. Interact., 42, 335-344... 

Miller, L. L., John, D. W. Nutritional, hormonal, and temporal factors regulating net plasma protein biosynthesis in the isolated perfused rat liver. In Plasma protein metabolism, pp. 207. Rothschild, M. A., Waldmann, T. (eds.). New York, London Academic Press 1970... 

When 32P-pDNA was constantly infused in the isolated perfused rat liver, however, its uptake by the perfused liver did not reach a steady state during the experimental period of 60 minutes (Yoshida et al., 1996). Therefore, a precise analysis of the binding and internalization characteristics could not be performed. 

R. W. Jansen, P. Olinga, G. Harms, and D. K. F. Meijer, Pharmacokinetic analysis and cellular distribution of the anti-HIV compound succinylated human serum albumin (Suc-HSA) in vivo and in the isolated perfused rat liver, Pharm. Res. 70 1611-1614 (1993). 

Anderson GD, Gidal BE, Kantor ED, et al. Lorazepam-valproate interaction studies in normal subjects and isolated perfused rat liver. Epilepsia 1994 35(l) 221-225. 

Booth CL, Brouwer KR, Brouwer KL. Effect of multidrug resistance modulators on the hepatobiliary disposition of doxorubicin in the isolated perfused rat liver. Cancer Res 1998 58(16) 3641-3648. 

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