Application of Organ Clearance to Estimation of the In Vivo Hepatic Extraction Ratio

The secretion of insulin into the portal blood and its removal by the liver and kidneys in conscious fed sheep were determined by simultaneously measuring venoarterial plasma concentration differences and portal, hepatic, and renal plasma flows. The basal secretory rate of insulin was 0.43 +/- 0.03 U/h or 7.8 mU/kg-h. The secretory rate of insulin and the amount of insulin presented to the liver also were altered by 2-h intraportal infusions of glucagon (150 mug/h), insulin (1.17 U/h), and insulin (1.17 U/h) lus glucose (2.2 g/h). Hepatic removal under all conditions was about 50% of the insulin secretory rate, although the extraction ratio was only 0.08. Renal removal was 35% of the insulin secretory rate. The renal extraction ratio was 0.35. During insulin-induced hypoglycemia and also during starvation, the hepatic extraction ratio of insulin increased significantly, but the removal as a percentage of insulin secretion did not change. It appears that in sheep on a maintenance diet the basal secretory rate of insulin is less than that of nonruminant species and that, within physiological limits, the liver disposes of about one-half and the kidney about one-third of the insulin. Other tissues, presumably, remove the remaining 10--20%.

Download Full-text

Variation in Hepatic Extraction Ratio with Unbound Drug Fraction: Discrimination Between Models of Hepatic Drug Elimination

Journal of Pharmaceutical Sciences ◽

10.1002/jps.2600740221 ◽

1985 ◽

Vol 74 (2) ◽

pp. 205-207 ◽

Cited By ~ 17

Author(s):

Amanda J. Byrne ◽

Denis J. Morgan ◽

Paul M. Harrison ◽

Allan J. McLean

Keyword(s):

Extraction Ratio ◽

Drug Elimination ◽

Hepatic Extraction ◽

Hepatic Drug ◽

Hepatic Extraction Ratio

Download Full-text

Ca2+ concentration influences the hepatic extraction of bioactive human PTH-(1-34) in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1989.256.1.e87 ◽

1989 ◽

Vol 256 (1) ◽

pp. E87-E92

Author(s):

P. D'Amour ◽

P. M. Huet

Keyword(s):

Liver Perfusion ◽

Extraction Ratio ◽

Hepatic Veins ◽

Gel Chromatography ◽

Hepatic Extraction ◽

Rat Liver Perfusion ◽

Chromatography Analysis ◽

System A ◽

Hepatic Extraction Ratio

The regulation of bioactive human parathyroid hormone [hPTH-(1-34)] hepatic extraction was studied in vitro by means of an isolated rat liver perfusion system. A standard buffer containing 20% red blood cells, 2% albumin, and variable concentrations of hPTH-(1-34) and Ca2+ was used in nonrecirculation experiments. Hepatic blood flow was kept constant at approximately 1.8 ml.g liver-1.min-1. hPTH in portal and hepatic veins was measured by a radioimmunoassay specific for hPTH-(1-34), and the results obtained were validated by gel chromatography analysis of the hormone measured. Results are expressed as mean +/- SD of five to six different experiments. In normocalcemic conditions (Ca2+ approximately 1.2 mmol/l), the hepatic extraction ratio of hPTH remained stable at 0.357 +/- 0.011 and 0.370 +/- 0.010 for hPTH-(1-34) concentrations of 0.156 +/- 0.002 and 1.314 +/- 0.014 pmol/ml; it decreased to 0.145 +/- 0.013 (P less than 0.001) for a hPTH-(1-34) concentration of 5.817 +/- 0.167 pmol/ml. Kinetics analysis of the normocalcemic data disclosed a Vmax of 1.971 +/- 0.18 pmol.min-1.g liver-1 and a Km of 1.410 +/- 0.39 pmol/ml. When hPTH-(1-34) concentration was kept stable with varying Ca2+ concentrations, elevated (1.62 +/- 0.01 mmol/l) Ca2+ gave an hepatic extraction ratio similar to normocalcemic conditions (0.335 +/- 0.014 vs. 0.357 +/- 0.011 mmol/l), whereas it significantly decreased in hypocalcemia (0.78 +/- 0.01 mmol/l) to 0.219 +/- 0.014 mmol/l (P less than 0.001). Kinetics were similar to normocalcemic conditions when Ca2+ concentration was elevated but appeared modified by hypocalcemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio

Drug Metabolism and Disposition ◽

10.1124/dmd.115.067595 ◽

2016 ◽

Vol 44 (7) ◽

pp. 1099-1102 ◽

Cited By ~ 15

Author(s):

F. Salem ◽

K. Abduljalil ◽

Y. Kamiyama ◽

A. Rostami-Hodjegan

Keyword(s):

Extraction Ratio ◽

Hepatic Extraction ◽

Hepatic Extraction Ratio ◽

Age Variation

Download Full-text

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

Clinical Science ◽

10.1042/cs0600065 ◽

1981 ◽

Vol 60 (1) ◽

pp. 65-72 ◽

Cited By ~ 18

Author(s):

I. T. Gilmore ◽

R. P. H. Thompson

Keyword(s):

Liver Disease ◽

Indocyanine Green ◽

Bile Acids ◽

Cholic Acid ◽

Enterohepatic Circulation ◽

Extraction Ratio ◽

Constant Infusion ◽

Hepatic Extraction ◽

Glycocholic Acid ◽

Hepatic Extraction Ratio

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.

Download Full-text

P-512 Evaluation of administration routes on hepatic extraction ratio of adriamycin using hepatic venous isolation and charcoal hemoperfusion

International Hepatology Communications ◽

10.1016/0928-4346(95)90809-l ◽

1995 ◽

Vol 3 ◽

pp. S165

Author(s):

M TOMINAGA

Keyword(s):

Extraction Ratio ◽

Hepatic Extraction ◽

Administration Routes ◽

Hepatic Extraction Ratio ◽

Charcoal Hemoperfusion

Download Full-text

Estimation of the Hepatic Extraction Ratio of Indocyanine Green in Swine

Clinical Science ◽

10.1042/cs0840681 ◽

1993 ◽

Vol 84 (6) ◽

pp. 681-685 ◽

Cited By ~ 4

Author(s):

David F. Kisor ◽

Reginald F. Frye ◽

Kenneth A. Kudsk

Keyword(s):

Indocyanine Green ◽

Pharmacokinetic Model ◽

Original Model ◽

Extraction Ratio ◽

Hepatic Extraction ◽

Glutathione S Transferase ◽

Time Data ◽

Model Estimate ◽

New Model ◽

Hepatic Extraction Ratio

1. The hepatic extraction ratio of Indocyanine Green was measured directly by trans-hepatic catheterization in 14 outbred swine (eight well-fed, six malnourished). A specific two-compartment pharmacokinetic model was fitted to the arterial Indocyanine Green concentration-time data and used to estimate the hepatic extraction ratio of Indocyanine Green. 2. The specific two-compartment pharmacokinetic model was modified to represent more accurately the physiological process of Indocyanine Green removal. Simulations were performed using this new model to estimate the hepatic extraction ratio of Indocyanine Green in the swine. 3. Similarly to previous findings, our data showed that the original model consistently overestimated the hepatic extraction ratio of Indocyanine Green (i.e. the model estimate was compared with the true, directly measured value). 4. The comparison of the modified model and the original model clearly indicates the reason for the overprediction of the hepatic extraction ratio of Indocyanine Green by the latter. The simulations using the new model indicate that the percentage of binding of Indocyanine Green to its transport protein (glutathione S-transferase) for removal in the bile will affect the estimation of the hepatic extraction ratio of Indocyanine Green. Thus, the amount of Indocyanine Green available for removal is less than that assumed by the original model.

Download Full-text