Kinetics of 14C-glycocholic acid clearance in normal man and in patients with liver disease.

Gilmore, Ian; Thompson, R. P. H.

doi:10.1136/gut.19.12.1110

Cited by 29 publications

(16 citation statements)

References 18 publications

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“…In vivo distribution and elimination processes rapidly reduce the serum concentrations of glycocholic acid injected. Distribution and elimination half-lives of around 2 and 10 min, respectively, have been observed for this bile acid in man after intravenous bolus injection (Cowen et al, 1975;Gilmore & Thompson, 1978). Dose-independence, i.e.…”

Section: Experimental Techniquesmentioning

confidence: 99%

“…Even after the highest investigated dose of 7.5 mg kg-1, glycocholic acid peripheral predose concentrations below 1 ,UM were achieved again within approximately 10 min. Moreover, the high hepatic extraction ratio for glycocholic acid (0.85; Gilmore & Thompson, 1978) assures rapid removal of this constituent. Nevertheless, it appears advisable to inject drug preparations solubilized with MM slowly, thereby lowering the concentrations of MM constituents present at any time in plasma and hence reducing the potential for an interaction with other drugs present in blood and highly bound to plasma proteins.…”

Section: Experimental Techniquesmentioning

confidence: 99%

See 1 more Smart Citation

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Oie

Paalzow

et al. 1987

Brit J Clinical Pharma

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Mixed micelles (MM) formed from glycocholic acid and lecithin are suited to solubilize lipophilic drugs for intravenous use. To test for possible drug‐drug interactions, the protein binding of a series of agents known to bind to different sites on albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and additionally (prazosin, quinidine, propranolol) or exclusively (disopyramide) to alpha 1‐acid glycoprotein or to transcortin (prednisolone) was determined in the presence and absence of MM. Concentrations of MM, corresponding to the maximum possible plasma concentration achieved by injecting the highest clinical doses of MM into the systemic circulation, had little or no effect on the unbound fractions of drugs known to bind exclusively to albumin. Only at five times higher MM concentrations were the free fractions substantially increased (by up to 45%). Unbound fractions of drugs bound with high affinity but low capacity to alpha 1‐acid glycoprotein were increased between 50‐85% even at ‘therapeutic’ doses of MM. The present study suggests that drugs solubilized by MM should be given by slow injection or infusion to patients already receiving drugs which are highly bound to alpha 1‐acid glycoprotein.

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Section: Experimental Techniquesmentioning

confidence: 99%

Section: Experimental Techniquesmentioning

confidence: 99%

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Oie

Paalzow

et al. 1987

Brit J Clinical Pharma

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“…The acceleration of the enterohepatic flow during digestion was signaled by a striking increase in the serum level of bile acids. With this information and other experimental evidence indicating that the fractional hepatic extraction of any given bile acid species remained relatively constant throughout the day (26)(27)(28)(29), it became possible to construct steady-state multicompartmental models (30,31) (32) and an Italian program of modeling and simulation of physiological processes (33,34). In future studies, we hope to apply the model to the other major primary and secondary bile acids and also to describe and simulate the disturbances in bile acid metabolism that may occur in liver and intestinal disease.…”

Section: Introductionmentioning

confidence: 99%

Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

Hofmann¹,

Molino²,

Milanese³

et al. 1983

J. Clin. Invest.

109

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A B S T R A C T A multicompartmental pharmacokinetic model based on physiological principles, experimental data, and the standard mathematical principles of compartmental analysis has been constructed that fully describes the metabolism and enterohepatic cycling in man of cholic acid, a major bile acid. The model features compartments and linear transfer coefficients. The compartments are aggregated into nine spaces based on physiological considerations (liver, gallbladder, bile ducts, jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). The transfer coefficients are also categorized according to function: flow, i.e., emptying of gallbladder or intestinal spaces, and circulation of the blood; biotransformation, i.e., conjugation, deconjugation, or dehydroxylation; and transport, i.e., active or passive transport. The model is made time dependent by introducing meals, which trigger discrete increases in gallbladder emptying and intestinal flow. Each space contains three compartments. For cholic acid, these are unconjugated cholic acid, cholylglycine, and cholyltaurine. The model was then used with all existing experimental data to simulate cholic acid metabolism in healthy man over a 24-h period. Satisfactory agreement was obtained between simulated and experimental results for serum bile acid levels, hepatic bile acid secretion, and bile acid secretion into the intestine. The model was also used to classify 16 clinical instances in which the enterohepatic circulation of bile acids is altered

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“…Extraction was in the normal range, however, in the single patient with viral hepatitis, and was little altered in some of the patients with anicteric chronic liver disease. The elimination of drugs with high hepatic extraction depends more on blood flow than on hepatocellular function (Wilkinson & Shand, 1975), and the plasma clearance of [14Clglyco-cholic acid is known to be insensitive for the detection of liver disease (Ferguson, Calcraft, Hofmann & Belobaba, 1976;Gilmore & Thompson, 1978). Paumgartner, Reichen & Preisig (1974) found the hepatic extraction ratio of [14C ltaurocholate to be 0·12-0· 79 in patients with cirrhosis studied before portacaval shunt surgery, but could not determine the extraction in some because of fluctuations in the extraction ratio.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma half-life times or percentage retention of the injected bile acid have been used as estimates of hepatic bile acid uptake, but these are at best approximations. More recently, the total volume of plasma cleared per unit time has been measured, and this use of clearance is preferable as it is uninfluenced by changes in distribution volume; with this measurement bile acid uptake has been found to be insensitive for the detection of anicteric liver disease (Gilmore & Thompson, 1978). Even plasma clearance, however, is not a direct reflection of hepatic bile acid uptake; it is influenced by extrahepatic removal, although this is usually small (Ng & Hofmann, 1977).…”

Section: Introductionmentioning

confidence: 98%

Direct Measurement of Hepatic Extraction of Bile Acids in Subjects with and without Liver Disease

Gilmore

Thompson

1981

Clinical Science

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1. The hepatic extraction ratio of 14C-labelled bile acids has been measured directly by hepatic vein catheterization in five patients without liver disease (glycocholic acid, three; cholic acid, two) and in 16 patients with histologically confirmed liver disease (glycocholic acid, seven; cholic acid, nine). 2. After intravenous administration of [14C]-glycocholic acid by bolus injection (two control subjects) or constant infusion (one control subject), directly measured hepatic extraction ratio was 0.91, 0.84 and 0.88, greater than that for indocyanine green. The extraction ratio of [14C]cholic acid in two subjects was 0.72 and 0.70, confirming a lower extraction of the unconjugated bile acid. 3. The hepatic extraction ratio of both bile acids was reduced in patients with chronic liver disease (range 0.07-0.69), although the extraction ratio of glycocholic acid remained normal in one patient with viral hepatitis. 4. Estimates of liver flow calculated from the extraction of [14C]glycocholic acid, but not cholic acid, correlated with those calculated from indocyanine green kinetics, although numbers were small. 5. Measurement of the hepatic extraction of individual bile acids, not previously reported in man, allows a more accurate description of the enterohepatic circulation.

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Kinetics of 14C-glycocholic acid clearance in normal man and in patients with liver disease.

Cited by 29 publications

References 18 publications

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

Direct Measurement of Hepatic Extraction of Bile Acids in Subjects with and without Liver Disease

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