Biliary Excretion of Dibromosulphthalein in the Freely Moving Unanaesthetized Rat: Circadian Variation and Effects of Deprivation of Food and Pentobarbital Anaesthesia

1978 ◽  
Vol 55 (4) ◽  
pp. 399-406 ◽  
Author(s):  
R. J. Vonk ◽  
E. Scholtens ◽  
J. H. Strubbe
Keyword(s):  
Biliary Excretion ◽  
Bile Flow ◽  
Enterohepatic Circulation ◽  
Circadian Variation ◽  
Hepatic Clearance ◽  
Circadian Variations ◽  
Hepatic Transport ◽  
Freely Moving ◽  
Biliary Excretion Rate ◽  
Pentobarbital Anaesthesia

1. In unanaesthetized, freely moving rats, which displayed a circadian rhythm in bile flow, hepatic transport of dibromosulphthalein was investigated at midnight when bile flow was high and at noon when bile flow was lower. The influence of pentobarbital anaesthesia and starvation on hepatic transport of dibromosulphthalein was also studied. The influence of bile salts on the hepatic transport process was investigated by interruption of the enterohepatic circulation. 2. Maximal biliary transport of dibromosulphthalein was subject to circadian variations: the biliary transport maximum at night was 25% higher than at noon, although maximal biliary concentration was not significantly altered. The distribution volume was increased by 21% during the night, but the primary hepatic clearance constant was not changed. 3. Pentobarbital anaesthesia decreased the maximal biliary concentration and the maximal biliary excretion rate of dibromosulphthalein, but the primary hepatic clearance constant was not changed. 4. Starvation for 48 h changed the primary hepatic clearance constant as well as the biliary excretion of dibromosulphthalein. 5. Interruption of the enterohepatic circulation of bile did not change the primary hepatic clearance constant of dibromosulphthalein, but decreased biliary excretion of the drug. 6. This study clearly indicates that time of the day, feeding conditions, the use of anaesthetics and interruption of the enterohepatic circulation of bile are important determinants in biliary excretion of cholephilic dyes.

Influence of bile salts on hepatic transport of dibromosulphthalein.

1979 ◽  
Vol 237 (6) ◽  
pp. E524
Author(s):  
R J Vonk ◽  
M Danhof ◽  
T Coenraads ◽  
A B van Doorn ◽  
K Keulemans ◽  
...  
Keyword(s):  
Biliary Excretion ◽  
Bile Flow ◽  
Bile Salts ◽  
Ethacrynic Acid ◽  
Organic Anion ◽  
Hepatic Uptake ◽  
Hepatic Transport ◽  
Intracellular Binding ◽  
Highly Correlated ◽  
Biliary Excretion Rate

The influence of bile salts on hepatic transport of the organic anion dibromosulphthalein (DBSP) was investigated in rats. Bile salts influence the hepatic uptake, intracellular binding, and biliary excretion of DBSP. The overall effect depends on the administered dose of bile salts and DBSP. High doses of bile salts inhibited hepatic uptake of DBSP, whereas low doses of bile salts stimulated bile flow and simultaneously increased maximal biliary excretion of DBSP. The uncharged nonbile salt choleretic ouabain also stimulated biliary DBSP excretion. In contrast, the anionic nonbile salt choleretics, ethacrynic acid and theophylline, did not stimulate biliary excretion of DBSP. Because DBSP inhibited biliary excretion of ethacrynic acid and its metabolites, the lack of a stimulatory effect of ethacrynic acid choleresis might be explained by concomitant inhibition of biliary excretion of DBSP, masking the stimulatory effect of ethacrynic acid. Biliary transport maximum of DBSP was highly correlated with bile flow. The biliary clearance (Vmax/Km) was only moderately changed by bile salt administration, whereas the increase in the maximal biliary excretion rate was more pronounced, implying that the apparent Km for biliary excretion of DBSP was also increased by the bile salts. It is inferred that the stimulation of net biliary excretion of DBSP by bile salts may be due to a diminished transport from bile into the hepatocytes as the consequence of the decreased biliary concentration caused by the choleresis.

Bile Secretion and Bile Composition in the Freely Moving, Unanaesthetized Rat with a Permanent Biliary Drainage: Influence of Food Intake on Bile Flow

1978 ◽  
Vol 55 (3) ◽  
pp. 253-259 ◽  
Author(s):  
R. J. Vonk ◽  
A. B. D. van Doorn ◽  
J. H. Strubbe
Keyword(s):  
Food Intake ◽  
Bile Salt ◽  
Bile Flow ◽  
Circadian Variation ◽  
Bile Secretion ◽  
Female Rats ◽  
Bile Composition ◽  
Influence Of Food ◽  
The Mean ◽  
Freely Moving

1. In freely moving, unanaesthetized rats bile flow was measured continuously over the whole day-night cycle. Bile composition was analysed and the influence of food intake on bile flow was investigated. 2. In both sexes a distinct circadian variation of bile production was observed. The mean night-time production was 50% higher than the day-time value for female rats and 38% for male rats. In the morning when the light was switched on, a sharp decrease in secretion rate was prominent and bile flow gradually increased in the afternoon. 3. The pattern of food intake was positively correlated with the pattern of bile secretion. During fasting only the general level of bile flow decreased, but the circadian variation persisted. Refeeding again increased the mean level of bile flow. 4. The chenodeoxycholate/cholate ratio in these rats with permanent bile fistulae was higher than in rats with ‘acute’ bile fistulae and changed during the day-night cycle. The ratio decreased from 1.01 at 05.00 hours to a minimum of 0.41 at 15.00 hours. 5. During the day-night cycle the sodium, potassium, calcium and cholesterol concentrations were relatively constant. The total bile salt concentration was only slightly changed, so that both the bile salt-dependent fraction and the bile salt-independent fraction were subject to about the same circadian variations.

Hepatic and ileal transport and effect on biliary secretion of norursocholic acid and its conjugates in rats

1991 ◽  
Vol 261 (6) ◽  
pp. G1057-G1064
Author(s):  
J. Lillienau ◽  
L. R. Hagey ◽  
B. Borgstrom
Keyword(s):  
Bile Acids ◽  
Bile Flow ◽  
Enterohepatic Circulation ◽  
Biliary Lipid ◽  
Perfusion Technique ◽  
Hepatic Transport ◽  
Rate Of Absorption ◽  
Cholesterol Secretion ◽  
Hepatic Biotransformation

The enterohepatic circulation of norursocholic acid (nUC) and its glycine (nUCG) and taurine (nUCT) conjugates was investigated in the rat; cholic acid (C) was studied as control. The biliary recovery of intravenously infused 14C-labeled bile acids was high: nUC, 88%; nUCG, 80%; nUCT, 99%, and C, 90%. Biliary recovery after the same bile acids were infused intraduodenally was similar: nUC, 90%; nUCG, 66%; nUCT, 97%; and C, 99%. The two conjugated bile acids, nUCG and nUCT, were not biotransformed during intestinal or hepatic transport; nUC was also secreted largely unchanged, but approximately 10% was secreted as an unknown conjugate or sulfate; C was completely conjugated with taurine or glycine. To compare the rates of active ileal transport, biliary recovery was measured after an in situ ileal perfusion technique. The rate of absorption of nUC, nUCG, and nUCT was one-fourth to one-half that of cholyltaurine, which served as control. Competition experiments indicated that the same transport system was involved. When infused intravenously, nUC, nUCG, and nUCT induced far less biliary lipid secretion than an identical dose of C; the secretion of both phospholipid and cholesterol was decreased, cholesterol to a greater extent than phospholipid. It is concluded that nUC and its conjugates are well transported by the ileum, are efficiently secreted into bile without undergoing appreciable hepatic biotransformation, and induce bile flow as other hydrophilic bile acids, but in contrast to C induce little phospholipid and cholesterol secretion into bile.

Cholestasis induced by Sulphated Glycolithocholic Acid in the Rat: Protection by Endogenous Bile Acids

1985 ◽  
Vol 68 (2) ◽  
pp. 127-134 ◽  
Author(s):  
Folkert Kuipers ◽  
Rick Havinga ◽  
Roel J. Vonk
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Biliary Excretion ◽  
Hepatic Clearance ◽  
Recovery Phase ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Hepatotoxic Effect ◽  
Biliary Excretion Rate ◽  
Bile Production

1. Sulphated glycolithocholic acid (SGLC) causes cholestasis in experimental animals, despite its sulphated form. In the present study, the cholestatic potency and the pharmacokinetics of SGLC were investigated in rats under two conditions: (a) in the presence of an intact circulating bile acid pool and (b) after exhaustion of the bile acid pool by 24 h of bile diversion. 2. Intravenous administration of SGLC (8 μmol/ 100 g body weight) to rats with an intact bile acid pool did not cause cholestasis. However, biliary phospholipid and cholesterol concentrations were reduced by 40% and 29% respectively during the first hour after administration. When the same dose of the bile acid was injected in rats with a 24 h biliary drainage, a complete cessation of bile production was observed within 1 h. Twelve hours after the onset of cholestasis, bile production gradually increased again, showed a marked overshoot, and reached control levels after 3 days. In the recovery phase, biliary phospholipid and cholesterol concentrations were greatly reduced. 3. The absence of endogenous bile acids did not change the hepatic clearance rate of a tracer dose of radiolabelled SGLC, but markedly decreased its biliary excretion rate. 4. It was concluded that the hepatotoxic effect of SGLC is much more pronounced in rats with an exhausted bile acid pool, possibly due to a slower biliary excretion of the toxic compound. This phenomenon may have clinical implications for patients with a contracted bile acid pool.

Pentobarbital Inhibits the Biliary Excretion of Organic Acids: a Study with Succinylsulfathiazole in the Rat

1975 ◽  
Vol 53 (3) ◽  
pp. 470-474 ◽  
Author(s):  
D. G. Bailey ◽  
H. Paul ◽  
G. E. Johnson
Keyword(s):  
Organic Acids ◽  
Biliary Excretion ◽  
Concentration Gradient ◽  
Bile Flow ◽  
Hepatic Transport ◽  
Acidic Drugs ◽  
Time Period ◽  
Liver Concentration

The present study was undertaken to determine whether the use of pentobarbital as an anesthetic reduces the biliary excretion of acidic drugs in rats. The drug chosen for the experiment was succinylsulfathiazole, a compound excreted unmetabolized in the bile. Animals anesthetized with urethane excreted 22.1% of the dose in the bile as compared to only 8.4% for the same time period in pentobarbital anesthetized animals. The choice of anesthetic did not affect the bile flow but did influence the bile/liver concentration gradient of succinylsulfathiazole, with the pentobarbital treated rats demonstrating a significantly lower value. Despite the higher biliary excretion of succinylsulfathiazole in the urethane treated rats, the total amount in the bile plus urine was 60% of the dose in the urethane anesthetized animals as compared with 62% in the pentobarbital treated rats. These results suggest that pentobarbital reduced the hepatic transport of succinylsulfathiazole into the bile. The question whether urethane is a preferred anesthetic for biliary excretion studies warrants further investigation.

Endotoxin-induced reduction in biliary indocyanine green excretion rate in a chronically catheterized rat model

2001 ◽  
Vol 280 (5) ◽  
pp. G858-G865 ◽  
Author(s):  
David W. A. Beno ◽  
Michael R. Uhing ◽  
Masakatsu Goto ◽  
Yong Chen ◽  
Vanida A. Jiyamapa-Serna ◽  
...  
Keyword(s):  
Indocyanine Green ◽  
Rat Model ◽  
Biliary Excretion ◽  
Bile Flow ◽  
Excretion Rate ◽  
Hepatic Function ◽  
Tnf Α ◽  
Biliary Excretion Rate ◽  
Factor Α ◽  
Change In Mean

Using a nonstressed chronically catheterized rat model in which the common bile duct was cannulated, we studied endotoxin-induced alterations in hepatic function by measuring changes in the maximal steady-state biliary excretion rate of the anionic dye indocyanine green (ICG). Biliary excretion of ICG was calculated from direct measurements of biliary ICG concentrations and the bile flow rate during a continuous vascular infusion of ICG. Despite significant elevations in mean peak serum tumor necrosis factor-α (TNF-α) concentrations (90.9 ± 16.2 ng/ml), there was no effect on mean rates of bile flow or biliary ICG clearance after administration of 100 μg/kg endotoxin at 6 or 24 h. Significant differences from mean baseline rates of bile flow and biliary ICG excretion did occur after administration of 1,000 μg/kg endotoxin (mean peak TNF-α 129.6 ± 24.4 ng/ml). Furthermore, when rats were treated with up to 16 μg/kg of recombinant TNF-α, there was no change in mean rates of bile flow or ICG biliary clearance compared with baseline values. These data suggest that the complex regulation of biliary excretion is not mediated solely by TNF-α.

Hepatic clearance of rat plasma intestinal alkaline phosphatase

1984 ◽  
Vol 247 (4) ◽  
pp. G419-G426 ◽  
Author(s):  
G. P. Young ◽  
I. S. Rose ◽  
S. Cropper ◽  
S. Seetharam ◽  
D. H. Alpers
Keyword(s):  
Alkaline Phosphatase ◽  
Biliary Excretion ◽  
Enterohepatic Circulation ◽  
Hepatic Clearance ◽  
Rat Plasma ◽  
Intestinal Alkaline Phosphatase ◽  
Rapid Clearance ◽  
Specific Receptors ◽  
Disappearance Curve ◽  
Plasma Disappearance Curve

The mechanism and route of clearance of intestinal alkaline phosphatase from plasma have been studied in rats to define the magnitude of hepatic extraction and biliary excretion of the enzyme. Plasma clearance, tissue distribution, and biliary excretion of enzyme were followed after intravenous administration of physiological amounts of 125I-labeled rat intestinal alkaline phosphatase. The plasma disappearance curve was biphasic; the initial phase was rapid, during which 50% of injected enzyme was selectively extracted by the liver over 5 min. Less than 4% of total hepatic radioactivity was excreted into bile over 80 min; this was shown by chromatographic analysis to be degraded enzyme only. Rapid clearance of enzyme could be significantly slowed by injection of large amounts of mannan or N-acetylglucosamine-bovine serum albumin, but not by desialylated fetuin, demonstrating that clearance was probably mediated by mannose/N-acetylglucosamine-specific receptors. It is concluded that, under physiological conditions, rat plasma intestinal alkaline phosphatase is rapidly cleared from the circulation by the liver. However, biliary excretion of undergraded enzyme is negligible, and a physiologically significant enterohepatic circulation seems most unlikely.

Bile Flow and Biliary Excretion Rate of Some Organic Anions in Phenobarbital-Pretreated Rats

Digestion ◽  
1978 ◽  
Vol 17 (3) ◽  
pp. 211-220 ◽  
Author(s):  
E. Fischer ◽  
F. Varga ◽  
Z. Gregus ◽  
A. Gógl
Keyword(s):  
Biliary Excretion ◽  
Bile Flow ◽  
Excretion Rate ◽  
Organic Anions ◽  
Biliary Excretion Rate

The effects of oral diazepam pretreatment on the biliary excretion of sulfobromophthalein in rats

1976 ◽  
Vol 54 (4) ◽  
pp. 603-612 ◽  
Author(s):  
George K. Hanasono ◽  
Louis De Repentigny ◽  
Brian G. Priestly ◽  
Gabriel L. Plaa
Keyword(s):  
Biliary Excretion ◽  
Bile Flow ◽  
Elimination Rate ◽  
Hepatic Uptake ◽  
Male Rats ◽  
Bile Formation ◽  
Biliary Excretion Rate ◽  
Oral Doses ◽  
Oral Diazepam

Studies were performed with rats to examine the effects of single, as well as repetitive oral diazepam (DZP) pretreatment on biliary sulfobromophthalein (BSP) excretion rates and on bile flow parameters. One-hour pretreatment of male rats with 150 mg/kg of DZP resulted in about a one-third reduction in the peak biliary excretion rate of BSP (60 mg/kg, iv) and this was associated with a decrease in relative proportions of conjugated to unconjugated BSP in bile. The biliary excretion of preconjugated BSP was unaffected. BSP hepatic uptake and storage were apparently unaffected. In vitro DZP markedly inhibited BSP conjugating activity.In contrast to the above results, when BSP excretion was examined 1 h after the last of five daily oral doses of DZP (150 mg kg−1 day−1), no change in the peak elimination rate of this dye was evident. However, bile flow rates were higher in DZP-treated rats than in controls.When rats were examined 24 h after the last of live daily oral doses of DZP (150 mg/kg), the choleretic response persisted. Further studies showed that the repetitive DZP pretreatment enhanced the bile salt-independent mechanisms of bile formation.

Mrp2 is involved in benzylpenicillin-induced choleresis

2004 ◽  
Vol 287 (1) ◽  
pp. G42-G49 ◽  
Author(s):  
Kousei Ito ◽  
Tomokazu Koresawa ◽  
Koichi Nakano ◽  
Toshiharu Horie
Keyword(s):  
Biliary Excretion ◽  
Bile Flow ◽  
Excretion Rate ◽  
Membrane Vesicles ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Concentration Dependent Manner ◽  
Sd Rats ◽  
Biliary Excretion Rate ◽  
Choleretic Effect

Benzylpenicillin (PCG; 180 μmol/kg), a classic β-lactam antibiotic, was intravenously given to Sprague-Dawley (SD) rats and multidrug resistance-associated protein 2 (Mrp2)-deficient Eisai hyperbilirubinemic rats (EHBR). A percentage of the [3H]PCG was excreted into the bile of the rats within 60 min (SD rats: 31.7% and EHBR: 4.3%). Remarkably, a transient increase in the bile flow (∼2-fold) and a slight increase in the total biliary bilirubin excretion were observed in SD rats but not in the EHBR after PCG administration. This suggests that the biliary excretion of PCG and its choleretic effect are Mrp2-dependent. Positive correlations were observed between the biliary excretion rate of PCG and bile flow ( r2 = 0.768) and more remarkably between the biliary excretion rate of GSH and bile flow ( r2 = 0.968). No ATP-dependent uptake of [3H]PCG was observed in Mrp2-expressing Sf9 membrane vesicles, whereas other forms of Mrp2-substrate transport were stimulated in the presence of PCG. GSH efflux mediated by human MRP2 expressed in Madin-Darby canine kidney II cells was enhanced in the presence of PCG in a concentration-dependent manner. In conclusion, the choleretic effect of PCG is caused by the stimulation of biliary GSH efflux as well as the concentrative biliary excretion of PCG itself, both of which were Mrp2 dependent.

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