Cholangiographic excretion studies: a comparison of iodipamide and iodoxamate in the dog

Iodoxamic acid is a new hexaiodinated cholegraphic contrast agent. The methylglucamine salts of iodoxamate and iodipamide were administered to labrador dogs as an intravenous infusion. Bile salts were also infused. The biliary concentration and output of the two agents were compared. Bile flow rate, bile salt concentration and bile salt output with the two agents were also compared. The biliary output of iodoxamate (0.70-0.78 mumol/min/kg) was more than 50% higher than the iodipamide output (0.46 mumol/min/kg). Bile salt output and concentration with iodoxamate infusion were lower than with iodipamide infusion. The bile flow rate was higher with the new agent. The complementary effects of increased contrast output and decreased bile salt output with the new agent led to a significantly higher biliary iodine concentration compared with iodipamide. The results of this study support the suggestion that iodoxamate represents a significant advance in the cholegraphic contrast media field.     

Pharmaco-cholangiography with anticholinergic drugs in the dog

The effect of atropine and pipenzolate bromide (PB) in different dosage levels was investigated in intravenous cholangiography with 0.6 ml/kg iodipamide infused over 30 minutes in six cholecystectomized dogs (20-36 kg) equipped with Thomas cannulas through which the common bile duct could be cannulated. Doses of 1 mg atropine and 20 mg PB, half the dose given intravenously just prior to the contrast agent and the other half with the iodipamide infusion, had the greatest effect in decreasing the bile flow (atropine-24% at 60, PB-23% at 30 minutes) and increasing the bile iodine concentration (atropine + 16%, PB + 14%). The biliary iodipamide excretion rate was not affected.     

The effect of paraben preservatives on albumin binding of bilirubin

The effect of sodium taurocholate in stepwise increasing infusion rates, 0.3 to 9.6 mumoles per min per kg, on the biliary excretion rate of iodipamide was investigated in 6 dogs (10 experiments) with complete bile diversion under general anesthesia. Iodipamide was administered intravenously with an initial priming dose of 33 mumoles per kg followed by a constant infusion of 1.3 mumoles per min per kg. Although the bile flow continuously increased with an increasing taurocholate dose, the iodipamide excretion rate reached a plateau with a 0.6 mumoles per min per kg of taurcholate infusion, which was 20% higher than with the lowest taurocholate dose. With a taurocholate dose over 2.4 mumoles per min per kg, a significant decrease in the iodipamide rate was found, amounting to 22% of its maximum value with the largest taurocholate dose. The bile iodipamide concentration was already at its maximum with the lowest taurocholate dose, and it decreased with an increasing taurocholate dose. Since the bile iodipamide concentration is probably the most important determinant in clinical cholangiography, low bile salt plasma levels should result in the best radiographic visualization of the biliary tree.     

Iodipamide kinetics: capacity-limited biliary excretion with simultaneous pseudo-first-order renal excretion

Iodipamide was infused into three dogs with bile fistulas to achieve various steady-state blood levels. When using ultracentrifugation techniques, iodipamide was found to be highly bound to plasma protein. The total blood clearance was low relative to hepatic blood flow. For either the whole blood concentration or the unbound concentration of iodipamide, the biliary excretion was shown to be capacity limited with a transport maximum, Tm, of approximately 1.0mumole/kg/min. The steady-state renal excretion rate, plotted against the whole blood concentration of iodipamide, resulted in a concave ascending curve, which could lead to the false conclusion that iodipamide was undergoing active renal tubular reabsorption. However, when corrected for plasma protein binding, a linear relationship was obtained, suggesting that the renal excretion of iodipamide is a pseudo-first-order process. The Michaelis-Menten parameters for the extrarenal elimination, when calculated using the whole blood concentration of iodipamide, led to a similar discrepancy compared to the parameter estimates obtained from biliary excretion rate data. This discrepancy can be eliminated when one uses the unbound concentration of iodipamide in the parameter estimates.     

The effects of castration and treatment with testosterone on the biliary excretion of (3H)aldosterone in rats

The rate of excretion of aldosterone radiometabolites into the bile duct cannulation, and the intravenous injection of (3H)aldosterone, was demonstrated to be markedly increased in male rats following castration. In 1 h, 72% of the injected 3H-radioactivity was excreted in the bile of castrated male rats compared with 26% in the intact male control rats. Castration of the males led to the increased biliary excretion of aldosterone metabolites and the elimination of the sex-dependence of this process in rats. The ovariectomy of female rats did not substantially increase the rate of excretion of aldosterone metabolites via the bile. Castrated male rats treated with testosterone excreted aldosterone metabolites into the bile at a slower rate. A similar treatment of ovariectomized female rats with testosterone also significantly slowed the rate of biliary excretion of the aldosterone metabolites. These findings suggest that the presence of androgens plays an important role in regulating the routes of hepatic metabolism of aldosterone and the rates of clearance of aldosterone and its metabolites from the plasma into the bile of rats.     

Biliary excretion of furosemide glucuronide in rabbits

Furosemide (F) was administered to rabbits intravenously and intraduodenaly and the biliary excretion was studied. The major metabolite excreted in bile was furosemide glucuronide (FG). F and acyl migration isomers of FG (FG-iso) were also excreted in bile. The biliary excretion rates of total F (F+FG+FG-iso) following intraduodenal administration of F were much smaller than those following intravenous administration. The fraction of (F+FG-iso) in bile following intraduodenal administration of F were larger than those following intravenous administration. Stability of FG or FG-iso in bile and supernatant solution of the duodenum homogenate of rabbits was studied. FG was unstable in both media and its degradation followed apparent first-order kinetics in both media. In bile, FG degraded to produce several FG-iso and F, while in the supernatant solution of the duodenum homogenate, it hydrolyzed immediately to F. FG-iso were hardly detected in the supernatant solution. These results indicated that FG excreted in bile degraded easily to FG-iso and F. FG might easily hydrolyze to F enzymatically in the duodenum, and the resultant F might be reabsorbed from the intestinal tract. Unabsorbed FG-iso and F might be excreted in the feces.     

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

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 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 five 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.     

Comparison of the biliary excretion of the four isomers of bilirubin-IX in Wistar and homozygous Gunn rats

The biliary excretion of the four isomers of bilirubin-IX was studied in Wistar rats (JJ) and homozygous Gunn rats (jj). Synthetic preparations of 14C-labelled pigments were used. 1. After intravenous administration, the alpha-isomer was rapidly excreted in conjugated form in bile of Wistar rats. In Gunn rats excretion was insignificant. In contrast, both rat species promptly excreted the non-alpha-isomers at rates that were comparable with that found for bilirubin-IXalpha in Wistar rats. 2. In normal rats about 16% of the beta- and delta-isomers and at least 50% of the gamma-isomer were excreted as ester conjugates of the injected parent bile pigments. Conjugation of the beta- and delta-isomers had occurred exclusively at the carboxyl groups of pyrrole ring D and C respectively. For bilirubin-IXgamma no preference for any carboxyl group could be established. 3. In homozygous Gunn rats the non-alpha-isomers were apparently excreted chemically unaltered. This suggests that, as for bilirubin-IXalpha, conjugation of the non-alpha-isomers is also deficient in Gunn rats.     

The molecular mechanism of temperature enhancement of proton magnetic relaxation rates in methaemoprotein solutions. III. The effect of sixth ligand in high-spin derivatives

Levels of cefazolin were determined in plasma, urine, bile, and cerebrospinal fluid in humans after a bolus intravenous injection and during a controlled, continuous intravenous infusion. All the patients were studied in a steady-state and crossover fashion. In plasma, the mean peak level after bolus injection (1.5 g) studied in 12 patients was 206.5 mug/ml; during continuous infusion (6 g daily), the mean level remained stable at 52.6 mug/ml. With bolus injection and continuous infusion, respectively, 89.7 and 86.3% of the administered dose of cefazolin were excreted in the urine of nine patients over the 6-h period considered. The levels of cefazolin in common bile duct bile were studied in six cholecystectomized patients. In bile collected during the two 3-h periods of the experiment, the mean concentration of the drug in the bile after bolus injection was 66.9 and 22.0 mug/ml, respectively; during continuous infusion, the corresponding biliary levels were 50.7 and 51.3 mug/ml, respectively. In four neurosurgical patients with an intraventricular catheter, neither bolus injection nor continuous infusion resulted in a demonstrable concentration of cefazolin in the cerebrospinal fluid. The continuous intravenous administration of cefazolin might have some advantage over the intravenous bolus intermittent injections. In plasma, the area under the curve is greater with continuous infusion than with bolus injection. In bile, the levels of cefazolin are more sustained with continuous infusion than with bolus injection. This approach to intravenous administration of cefazolin deserves more pharmacological and clinical trials.     

Effect of ethynylestradiol on biliary excretion of bile acids, phosphatidylcolines, and cholesterol in the bile fistula rat

The effects of ethynylestradiol on endogenous bile acids, their capacity to conjugate and excrete intravenously infused cholic acid, the concentrations of biliary cholesterol and lecithin, and the individual molecular species of phosphatidylcholine have been determined in male and female Sprague-Dawley rats. Endogenous biliary bile acids were analyzed by gas-liquid chromatography-mass spectrometry. Eleven bile acids were identified and several minor bile acids, primarily muricholates, could not be completely characterized. After 5 days of treatment with ethynylestradiol (1 mg/kg per day), the percentage of cholic acid decreased and the percentage of 6beta-hydroxylated bile acids, including several monounsaturated species, increased. Ethynylestradiol caused a decrease in bile acid-independent bile flow. Intravenous infusion of cholic acid at a high concentration caused cholestasis in control animals but, after ethynylestradiol treatment, cholestasis developed during the infusion of a much lower concentration of cholate, indicating a lowered threshhold for bile acid-induced cholestasis. In the treated rats, there was a slight increase in excretion of unconjugated endogenous bile acids, and a striking impairment of conjugation of intravenously administered cholic acid. One of the few sex-related differences observed was an increased concentration of biliary phospholipids in untreated male rats. Both phospholipid and cholesterol concentrations in the bile were higher in the treated animals. The molar percentage of cholesterol was always 1-2%, but it was slightly higher in treated animals, especially males. Ethynylestradiol treatment also affected biliary phospholipid by causing a marked increase of phosphatidylcholine species containing palmitic and oleic acid residues and a decrease of species containing stearic and linoleic acid residues. There was no increase in biliary excretion of long chain polyunsaturated species, which might have indicated damage to membranes, in response to ethynylestradiol either alone or with cholic acid infusion. Some of these ethynylestradiol-induced changes in biliary bile acid and lipid excretion are probably peculiar to the rat, but others, such as the increase in molar percentage of cholesterol and cholestasis, may be relevant to disorders in man, especially cholesterol gallstones and idiopathic cholestasis of pregnancy.     

Computed tomographic cholangiography in the diagnosis of choledocholithiasis in severe bilirubinemia

Cholangiography used with oral or intravenous contrast agents has gained wide acceptance as the most objective preoperative diagnostic technique for choledocholithiasis. However, an indirect contrasting technique has been found quite unfit in patients with severe bilirubinemia. Despite this, the authors employed indirect contrasting of the bile ducts in 104 patients with severe bilirubinemia in combination with computed tomographic cholangiography. Contrasting took place in 90 (86.5%) patients. In complete obstruction of the choledochus (10 patients), intraductal hypertension prevents the contrast agent and bile from entering the hepatic ducts and the contrast agent is excreted by the kidneys. Thus, the use of the latest equipment and computers allows one to detect minor biliary contrast concentrations during indirect contrasting of the biliary tract in severe bilirubinemia.     

Biliary and pancreatic excretion of etoposide

Although biliary excretion of Etoposide is thought to be one of the main excretory routes, less investigation has been performed in human because of the clinical difficulties of bile collection. In the present study, the biliary and pancreatic excretion of Etoposide was examined through the hepaticus- or pancreaticus drainage in two pancreatoduodenectomized patients. The drug (95 mg) was infused for 30 min. Blood, bile and pancreatic juice were taken consecutively during and after infusion. Etoposide in the samples was measured as an unchanged type by HPLC. Etoposide was detected in the bile at the same level or more of the blood, their correlation being significant during the observation period. Recovery of the unchanged drug from the hepatic bile in the present series was 2.7-3.0% during the period of 3.5 hrs. And total recovery was estimated as 3.5-4.0% from AUC of the further extended concentration curve. Pancreatic excretion of Etoposide was minimum, its ratio with blood concentration being 2-3%. Recovery for 3.5 hrs. was less than 0.02%. From the data obtained, the biliary excretion of Etoposide was discussed together with its metabolites.     

Balloon catheter systems for PTCA: the importance of the catheter length

This complex study was designed to measure the transport and excretion characteristics of gadolinium ethoxybenzyl diethylenetriaminepentacetic acid (Gd-EOB-DTPA) in dog's livers following bolus and infusion. Simultaneous T1 magnetic resonance imaging was performed to measure maximum signal enhancement. Anaesthetized dogs had cannulation of the common bile duct and urinary bladder for collections and cannulation of the femoral artery and vein for monitoring, blood sampling and infusion. Gd-EOB-DTPA was administered by bolus (range 12.5-200 mumol/kg) and infusion (range 0.4-6.4 mumol/min per kg). An hepatic transport maximum 0.09-0.15 mumol/min/kg was achieved with a blood concentration of 0.03-0.06 mumol/mL. Marked hepatic affinity for Gd-EOB-DTPA was demonstrated with measurements of liver concentration. Maximum T1 signal enhancement was achieved with blood Gd-EOB-DTPA concentration of 0.02-0.03 mumol/mL and a liver concentration of 1-2 mumol/g. The transport maximum for Gd-EOB-DTPA in the dog was similar to that for ipodate and iodipamide and effective imaging was achieved with sub-maximal doses. The maximum signal enhancement at blood concentrations less than required for maximum transport suggest a wide latitude for effective clinical imaging.     

Reconstitution of cutaneous neural-immunological networks following bone marrow transplantation

Examination was made of the urinary and biliary excretion of the metabolites of genistein and genistein, the major components of Glycine and Sophora genus in rats. The urine of rats administered genistein orally contained eight metabolites. Three of these metabolites, genistein 4'-O-sulfate (M-1), genistein 7-O-beta-D-glucuronide (M-3), genistein 4'-O-sulfate 7-O-beta-D-glucuronide (M-6), were identified from spectroscopic and chemical data. The bile of rats administered genistein orally contained M-2, M-3 and M-6. M-6, a major biliary metabolite, was isolated and identified from spectroscopic and chemical data. The urine or bile of rats treated with genistein, the glycoside of genistein, contained M-1-M-8 or M-2, M-3, M-6 in the above metabolites. These findings suggest that genistein is absorbed as genistein after hydrolysis in the gastrointestinal tract. The total cumulative amounts of the two metabolites and genistein excreted in the urine during 48h, or of M-6 excreted in the bile during 36h following the oral administration of genistein, were approximately 5.7% or 16.0% of the doses administered, respectively. The result show that M-1, M-3 and M-6, having a free hydroxyl, glucuronide- or sulfate-conjugated hydroxyls at the C-7 or C-4' position, are excreted in the urine and bile as parts of the metabolites of genistein.     

Biliary excretion of dolichols and beta-hexosaminidase--effect of ethanol and glucagon

Alcohol has been reported to increase the urinary excretion of dolichols, and urinary dolichols are suggested to be derived from the lysosomes of the renal cells. In the present study we examined the effects of alcohol and glucagon on the biliary excretion of dolichols in rats. Chronic ethanol treatment decreased both biliary dolichol and beta-hexosaminidase excretion. The absolute amount of dolichol excreted into the bile correlated highly significantly with the absolute amount of biliary beta-hexosaminidase. Our results indicate that biliary dolichols are--at least in part--derived from hepatic lysosomes. Decreased biliary dolichol output during chronic alcohol administration suggests that urinary and biliary dolichol excretions are regulated independently of each other.     

The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis

Bilioma is a rare complication of traumatic liver injury, and the precise site of bile leak is often difficult to demonstrate with a non-invasive technique. We report a case of post-traumatic bile leak in a 15-year-old girl in whom spiral CT after intravenous cholangiography allowed excellent preoperative demonstration of the extent of the liver rupture and an exact location of the bile leak. We think that spiral-CT cholangiography could be an accurate, non-invasive technique to investigate the biliary system in cases of paediatric liver trauma.     

Localization of d-tubocurarine in rat liver lysosomes. Lysosomal uptake, biliary excretion and displacement by quinacrine in vivo

In the rat d-tubocurarine is taken up by the liver and excreted in bile. A fraction of the drug is taken up very rapidly by lysosomes. This lysosomal localization of the drug was demonstrated by purification of Triton WR 1339 loaded lysosomes ('tritosomes') on a sucrose density gradient by flotation; 3H-labeled d-tubocurarine was accumulated in the same fractions as acid phosphatase activity. Lysosome-bound d-tubocurarine is not available for biliary excretion and remains in the lysosomes even when the cytosolic concentration decreases to very low levels. The biliary excretion rate was linearly related to the amount of d-tubocurarine present in the cytosol. Lysosomal uptake of d-tubocurarine was decreased or prevented by the basic drug quinacrine in vivo. The lysosomal storage of d-tubocurarine is discussed in relation to its relevance for the clinical use of this and related drugs.     

Characterization of methylumbilliferone (mendiaxon r)-induced choleresis in the isolated perfused rat liver

The influence of the choleretic drug methylumbilliferone on bile formation in the isolated perfused rat liver is characterized. The compound induces rapidly an elevation of bile flow, bile acid secretion and soium excretion. The increased production of bile is of canalicular origin. The choleretic effect was defined as "bile acid like" choleresis due to excretion of the drug into the bile. It is discussed that the excretion of methylumbilliferone can influence the transport of bile in form of a positive cooperation on transport mechanism.     

Biliary excretion of cobalt in rats

The excretion of 58Co2+ via bile, urine and intestinal wall after intravenous administration of 58CoCl2 in two doses (177 and 1770 micrograms of Co2+ per kg B. Wt.) was studied in rats. The cumulative biliary excretion reached 24 hours after administration of lower dose 2.67 +/- 1.98% and higher dose 7.33 (4.6-10.9) % of the amount given. The highest excretion rate of 58Co was detected between 10 and 30 minutes after administration. After administration of higher dose of 58Co the lower urinary excretion was observed [73.6 +/- 4.0% resp. 47.9% (45.5-52.5)] of the amount given. There were no differences between both doses studied in the excretion of 58Co via the wall of gastrointestinal tract.     

Granulocyte colony-stimulating factor enhances endotoxin-induced decrease in biliary excretion of the antibiotic cefoperazone in rats

We have recently reported that endotoxin (lipopolysaccharide [LPS]) derived from Klebsiella pneumoniae dramatically decreased the biliary excretion of the beta-lactam antibiotic cefoperazone (CPZ), which is primarily excreted into the bile via the anion transport system, in rats. The present study was designed to investigate the effect of human recombinant granulocyte colony-stimulating factor (G-CSF), which is reported to be beneficial in experimental models of inflammation, on the pharmacokinetics and biliary excretion of CPZ in rats. CPZ (20 mg/kg of body weight) was administered intravenously 2 h after the intravenous injection of LPS (250 microgram/kg). G-CSF was injected subcutaneously at 12 microgram/kg for 3 days and was administered intravenously at a final dose of 50 microgram/kg 1 h before LPS injection. Peripheral blood cell numbers were also measured. LPS dramatically decreased the systemic and biliary clearances of CPZ and the bile flow rate. Pretreatment with G-CSF enhanced these decreases induced by LPS. The total leukocyte numbers were increased in rats pretreated with G-CSF compared to the numbers in the controls, while the total leukocyte numbers were decreased (about 3,000 cells/microliter) by treatment with LPS. Pretreatment with G-CSF produces a deleterious effect against the LPS-induced decrease in biliary secretion of CPZ, and leukocytes play an important role in that mechanism.