An Optimized Model for Rat Liver Perfusion Studies

Cheung, Kee; Hickman, Peter E.; Potter, Julia M.; Walker, Neal I.; Jericho, Megan; Haslam, Ross; Roberts, Michael S.

doi:10.1006/jsre.1996.0376

Cited by 62 publications

(58 citation statements)

References 6 publications

(2 reference statements)

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“…In this study, the oxygen consumption by the perfused caudal lobe of the ovine liver agrees well with the in vivo data . The value of the wet:dry weight ratio obtained in the present study is similar to those reported by Exton & Park (1967) and by Cheung et al (1996). The former reported a ratio of 3.78 in fasted rats before perfusion and 3.85 after 2 h of perfusion.…”

Section: Discussionsupporting

confidence: 92%

“…It is generally accepted that the most important factor in determining the viability of the isolated perfused lobe is a sufficient supply of oxygen (Gores et al 1986;Cheung et al 1996). In all our preparations, we started the perfusion of the lobe in situ to prevent any hypoxic injury and to eliminate any blood clotting.…”

Section: Discussionmentioning

confidence: 99%

“…The results clearly show that Oµ supply and consumption were constant throughout the perfusion. Oxygen consumption by the perfused rat liver has been reported to vary from 2 to 2.6 ìmol min¢ g¢ Cheung et al 1996), with lower values (1 ìmol min¢ g¢) associated with fasted rats (Gores et al 1986). In the present study, the oxygen consumption ranged from 1.6 to 2.4 ìmol min¢ g¢.…”

Section: Discussionmentioning

confidence: 99%

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Development of an improved technique for the perfusion of the isolated caudal lobe of sheep liver

et al. 2000

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Development of an improved technique for the perfusion of the isolated caudal lobe of sheep liver

et al. 2000

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“…The in situ rat liver perfusions were conducted using a standard procedure as outlined previously. 17 Briefly, rats were anesthetized by intraperitoneal injection of xylazine 10 mg ⅐ kg Ϫ1 (Bayer Australia, Pymble NSW, Australia) and ketamine hydrochloride 80 mg ⅐ kg Ϫ1 (Parnell Laboratories Australia Alexandria NSW, Australia). Following laparotomy, animals were heparinized (200 U heparin sodium; David Bull Laboratories Australia Mulgrave Victoria, Australia) via the inferior vena cava.…”

Section: Methodsmentioning

confidence: 99%

Quantitative evaluation of altered hepatic spaces and membrane transport in fibrotic rat liver

et al. 2002

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Four animal models were used to quantitatively evaluate hepatic alterations in this study: (1) a carbon tetrachloride control group (phenobarbital treatment only), (2) a CCl 4 -treated group (phenobarbital with CCl 4 treatment), (3) an alcohol-treated group (liquid diet with alcohol treatment), and (4) a pair-fed alcohol control group (liquid diet only). At the end of induction, single-pass perfused livers were used to conduct multiple indicator dilution (MID) studies. Hepatic spaces (vascular space, extravascular albumin space, extravascular sucrose space, and cellular distribution volume) and water hepatocyte permeability/surface area product were estimated from nonlinear regression of outflow concentration versus time profile data. The hepatic extraction ratio of 3 H-taurocholate was determined by the nonparametric moments method. Livers were then dissected for histopathologic analyses (e.g., fibrosis index, number of fenestrae). In these 4 models, CCl 4 -treated rats were found to have the smallest vascular space, extravascular albumin space, 3 H-taurocholate extraction, and water hepatocyte permeability/surface area product but the largest extravascular sucrose space and cellular distribution volume. In addition, a linear relationship was found to exist between histopathologic analyses (fibrosis index or number of fenestrae) and hepatic spaces. The hepatic extraction ratio of 3 H-taurocholate and water hepatocyte permeability/surface area product also correlated to the severity of fibrosis as defined by the fibrosis index. In conclusion, the multiple indicator dilution data obtained from the in situ perfused rat liver can be directly related to histopathologic analyses. (HEPATOLOGY 2002;36:1180-1189 L iver fibrosis and cirrhosis represent a major worldwide health problem. In cirrhosis, the normal hepatic lobular architecture is replaced by interconnecting bands of fibrous tissue surrounding nodules of regenerating hepatocytes. The sinusoidal stellate cell is central to the fibrotic process. 1-4 Consequently, extravascular space accessible to macromolecules (e.g., albumin) decreases and the distribution of sucrose shows a barrierlimited pattern in the space of Disse instead of the normal flow-limited behavior due to 3 hepatic alterations: (1) collagenization of the space of Disse, (2) formation of a basement membrane of the sinusoid (capillarization), and (3) intrahepatic, portahepatic shunt formation. 5-8 A liver biopsy is currently mandatory to assess severity of fibrosis.We recently examined the drug structure/disposition kinetics of a series of cationic drugs in carbon tetrachloride-and alcohol-induced fibrosis in perfused rat livers. 9 In this case, cationic drug disposition in the fibrotic liver can be predicted from drug properties and liver histopathology. As a result, the question was raised of whether we could use histopathology from patient liver biopsy specimens to estimate changes in hepatic spaces and whether the active and passive transport of probes (e.g., 3 H-taurocholate, 3 H-water) across ...

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“…Lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide) extraction ratio across the liver was employed to measure the viability for the efficiency of hepatic metabolism (25,27). Lidocaine (4 mg) was first dissolved in 1 ml ethanol, and then diluted to 3.53 mg/l with perfusate.…”

Section: Lidocaine Extractionmentioning

confidence: 99%

Pharmacokinetic Modeling of Absorption Behavior of 9-Aminocamptothecin (9-AC) Released from Colon-specific HPMA Copolymer–9-AC Conjugate in Rats

et al. 2007

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Purpose-To quantitate and predict colon-specific 9-aminocamptothecin (9-AC) release from the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-9-AC conjugate and its absorption behavior after oral administration in rats.Methods-Drug distribution in the gastrointestinal (GI) tract and the plasma concentration-time profile of 9-AC released from the HPMA copolymer conjugate were predicted using the degradation, transit, and absorption rate constants in cecum. The fate of 9-AC in cecum and liver was measured by in-situ cecum absorption and liver perfusion.Results-Following oral administration of the conjugate, 9-AC was released rapidly in cecum. Based on the pharmacokinetic model, up to 60% of the dose was in the cecum at ∼6 h, and 7% of the dose still remained there at 24 h. The predicted plasma concentration curve for released 9-AC after an oral dose of 3 mg/kg of 9-AC equivalent increased gradually and reached a peak of 98 nM at 7 h, then started decreasing slowly to 16 nM at 24 h. The bioavailability value was estimated as 0.31 after the first-pass elimination.Conclusions-A pharmacokinetic model delineated the impact of GI transit, drug absorption rate, and first-pass metabolism on drug disposition following oral administration of HPMA copolymer-9-AC conjugate in rats.

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An Optimized Model for Rat Liver Perfusion Studies

Cited by 62 publications

References 6 publications

Development of an improved technique for the perfusion of the isolated caudal lobe of sheep liver

Development of an improved technique for the perfusion of the isolated caudal lobe of sheep liver

Quantitative evaluation of altered hepatic spaces and membrane transport in fibrotic rat liver

Pharmacokinetic Modeling of Absorption Behavior of 9-Aminocamptothecin (9-AC) Released from Colon-specific HPMA Copolymer–9-AC Conjugate in Rats

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