Multiple Hepatic Excretory Mechanisms for Organic Anions. A Study with Succinylsulfathiazole and Taurocholate in the Rat

1975 ◽  
Vol 53 (1) ◽  
pp. 97-103 ◽  
Author(s):  
D. G. Bailey ◽  
G. E. Johnson
Keyword(s):  
Transport System ◽  
Intravenous Administration ◽  
Biliary Excretion ◽  
Plasma Proteins ◽  
Bile Flow ◽  
Plasma Concentrations ◽  
Concomitant Administration ◽  
Organic Anions ◽  
Excretion Rates ◽  
Acidic Compounds

A study was done to investigate interactions in the biliary excretion of [14C] succinylsulfathiazole and [3H]taurocholate after intravenous administration of the two compounds to anesthetized rats. Either compound administered alone increased bile flow and was excreted in the bile. The simultaneous infusion of both significantly increased bile flow above the values seen when either was given alone. However, the biliary-excretion rates of both compounds and their concentrations in bile were reduced when they were administered concomitantly. The simultaneous injection of radioactive taurocholate and succinylsulfathiazole did not alter significantly the plasma concentrations of either compound or their binding to plasma proteins from the values obtained when each was given alone. These results are consistent with a concept of competition between these compounds for the same liver-to-bile transport system. They contrast with previous observations that indicated that the concomitant administration of taurocholate increased the biliary excretion of acidic compounds. In the light of this work, it might be suggested that there are more than one transport system for the biliary excretion of organic anions.

The Influence of [3H]Taurocholate on the Biliary Excretion of [14C]Acetylprocaine Amide Ethobromide

1975 ◽  
Vol 53 (5) ◽  
pp. 888-894 ◽  
Author(s):  
S. H. Kuo ◽  
G. E. Johnson
Keyword(s):  
Biliary Excretion ◽  
Concentration Ratio ◽  
Jugular Vein ◽  
Sodium Taurocholate ◽  
Concomitant Administration ◽  
Plasma Concentration Ratio ◽  
Male Wistar Rats ◽  
The Common ◽  
Excretion Rates ◽  
Bile Samples

The biliary excretion rates of [14C]acetylprocaine amide ethobromide (acetyl-PAEB) and [3H]taurocholate, either administered alone or in combination to adult male Wistar rats, were studied. Their renal pedicles were ligated, and the common bile duct and one jugular vein cannulated. Acetyl-PAEB, 20 mg/kg, and sodium taurocholate, 70 mg/kg, were infused over a 5-min period. Blood and bile samples were collected every 10 min for 60 min. Liver samples were taken at 10 and 20 min. Approximately 100% of the administered taurocholate was excreted within 50 min. The simultaneous administration of acetyl-PAEB did not significantly alter the taurocholate excretion. The amount of the acetyl-PAEB dose excreted in 1 h was 9.4%. This was increased significantly to 16.5% when taurocholate was given concomitantly. The concentration of acetyl-PAEB in the bile increased significantly when taurocholate was given, and the ratios of its concentrations in bile–liver and bile–plasma were also increased. Taurocholate did not alter the liver–plasma concentration ratio of acetyl-PAEB. It is suggested that the concomitant administration of taurocholate increased the biliary excretion of acetyl-PAEB by facilitating its secretion by the liver into the bile.

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

Renal and hepatic excretions of phenol red and Bromsulphalein in the dog

1963 ◽  
Vol 204 (5) ◽  
pp. 776-780 ◽  
Author(s):  
Tai Ha Woo ◽  
Suk Ki Hong
Keyword(s):  
Urinary Excretion ◽  
Energy Dependence ◽  
Transport System ◽  
Biliary Excretion ◽  
Bile Flow ◽  
Phenol Red ◽  
Dehydrocholic Acid ◽  
Anesthetized Dogs

Effects of acetate, 2,4-dinitrophenol (DNP), Diodrast, dehydrocholic acid, and Na taurocholate on the urinary and biliary excretions of phenol red (PSP) and Bromsulphalein (BSP) were studied in 36 anesthetized dogs. Acetate increased the urinary excretion of both dyes as well as the biliary excretion of PSP whereas it had no effect on the biliary excretion of BSP. 2,4-DNP suppressed the urinary excretion of both dyes while it greatly increased the biliary excretion of PSP which was accompanied by an increase in the bile flow. However, the biliary excretion of BSP was increased only slightly by 2,4-DNP even though bile flow increased greatly. Diodrast, dehydrocholic acid, and Na taurocholate uniformly reduced both urinary and biliary excretions of PSP and BSP. Although some of these effects could be related to a corresponding change in bile flow, there was no consistent parallelism between the changes in dye excretion and in urine or bile flow. On the basis of these results, it is postulated that both the kidney and liver secrete PSP and BSP through a similar transport system. The energy dependence of this system could not be clearly ascertained from the present study.

scholarly journals Pregnancy-Related Effects on Nelfinavir-M8 Pharmacokinetics: a Population Study with 133 Women

2006 ◽  
Vol 50 (6) ◽  
pp. 2079-2086 ◽  
Author(s):  
Déborah Hirt ◽  
Jean-Marc Treluyer ◽  
Vincent Jullien ◽  
Ghislaine Firtion ◽  
Hélène Chappuy ◽  
...  
Keyword(s):  
Population Study ◽  
Time Course ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Concomitant Administration ◽  
Individual Characteristics ◽  
Individual Treatment ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Linear Absorption

ABSTRACT A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h−1; absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL10/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL1M/F), 0.65 liters/h (69%); and M8 elimination rate constant (k M0), 3.3 h−1 (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h−1) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.

Relationship of Bile Salts and Bile Flow to Biliary Excretion of Iopanoic Acid

1972 ◽  
Vol 7 (1) ◽  
pp. 11-15
Author(s):  
Albert A. Moss ◽  
John R. Amberg ◽  
Scott R. Jones
Keyword(s):  
Biliary Excretion ◽  
Bile Flow ◽  
Bile Salts ◽  
Iopanoic Acid ◽  
Relationship Of

Lack of Analgesic Activity of Morphine-6-glucuronide after Short-term Intravenous Administration in Healthy Volunteers 

1997 ◽  
Vol 87 (6) ◽  
pp. 1348-1358 ◽  
Author(s):  
Jorn Lotsch ◽  
Gerd Kobal ◽  
Anne Stockmann ◽  
Kay Brune ◽  
Gerd Geisslinger ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Analgesic Activity ◽  
Intravenous Administration ◽  
Opioid Analgesic ◽  
Plasma Concentrations ◽  
Experimental Pain ◽  
Controlled Study ◽  
Short Term ◽  
Analgesic Effects ◽  
Relative Contribution

Background The analgesic activity of morphine-6-glucuronide (M-6-G) is well recognized for its contribution to the effects of morphine and its possible use as an opioid analgesic with a wider therapeutic range than morphine. The present study attempted to quantify the relative contribution of M-6-G to analgesia observed after systemic administration of morphine. Methods In a placebo-controlled, sixfold crossover study in 20 healthy men, the effects of M-6-G were assessed at steady-state plasma concentrations of M-6-G identical to and two and three times higher than those measured after administration of morphine. Morphine and M-6-G were administered as an intravenous bolus followed by infusion over 4 h. Dosage A was M-6-G-bolus of 0.015 mg/kg plus infusion of 0.0072 mg x kg(-1) x h(-1). Dosage B was M-6-G-bolus of 0.029 mg/kg plus infusion of 0.014 mg x kg(-1) x h(-1). Dosage C was M-6-G-bolus of 0.044 mg/kg plus infusion of 0.022 mg x kg(-1) x h(-1). Dosage D was a morphine bolus of 0.14 mg/kg plus infusion of 0.05 mg x kg(-1) x h(-1) for 4 h. Dosage E was M-6-G combined with morphine (doses A + D). Dosage F was a placebo. The analgesic effects of M-6-G and morphine were measured before administration of the bolus and after 3.5 h using an experimental pain model based on pain-related cortical potentials and pain ratings after specific stimulation of the nasal nociceptor with short pulses of gaseous carbon dioxide. Results Morphine significantly reduced subjective and objective pain correlates compared with placebo. In contrast, M-6-G produced no statistically significant effects. The addition of M-6-G to morphine did not increase the effects of morphine. Morphine produced significantly more side effects than M-6-G. Conclusion After short-term intravenous administration at doses that produce plasma concentrations of M-6-G similar to those seen after administration of morphine, M-6-G had no analgesic effects in the present placebo-controlled study in healthy volunteers.

Isavuconazole: Case Report and Pharmacokinetic Considerations

Chemotherapy ◽  
2018 ◽  
Vol 63 (5) ◽  
pp. 253-256 ◽  
Author(s):  
Francesco Marchesi ◽  
Corrado Girmenia ◽  
Bianca Maria Goffredo ◽  
Emanuela Salvatorelli ◽  
Atelda Romano ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Plasma Concentrations ◽  
Real Life ◽  
Concomitant Administration ◽  
Invasive Fungal Disease ◽  
High Plasma ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Hepatic Toxicity ◽  
Maintenance Chemotherapy

Invasive fungal disease (IFD) is one of the major causes of morbidity and mortality in immunocompromised patients. Voriconazole (VCZ) and posaconazole (PCZ) remain the most widely used antifungals for the prophylaxis and treatment of IFD. However, VCZ and PCZ are liable for drug-drug interactions and show a pharmacokinetic variability that requires therapeutic drug monitoring (TDM). Isavuconazole (IVZ) is a newest generation triazole antifungal approved for the treatment of invasive aspergillosis (IA) in adult patients and for the treatment of invasive mucormycosis in adult patients for whom treatment with amphotericin B is inappropriate. In clinical trials, IVZ showed linear pharmacokinetics and little or no evidence for interactions with other drugs. There is only modest evidence on IVZ pharmacokinetics and TDM in real-life settings. Here, we report on IVZ pharmacokinetics in a young adult with Ph chromosome-negative acute lymphoblastic leukemia (ALL) who developed a “probable” IA during induction chemotherapy. The patient was initially treated with VCZ, but she developed a severe hepatic toxicity that was associated to the high plasma levels of VCZ. Therefore, VCZ was discontinued and the patient was switched to IVZ. After a loading dose of IVZ, the patient remained on IVZ for 5 months while also receiving standard maintenance chemotherapy for ALL. At day 65 after the start of IVZ, the patient experienced a significant hepatic toxicity; however, no change in IVZ plasma concentrations was observed in the face of a concomitant administration of many other drugs (cancer drugs, antiemetics, other anti-infectives). Hepatic toxicity resolved after discontinuing maintenance chemotherapy but not IVZ. These results show that (i) IVZ plasma concentrations remained stable throughout and were not affected by concomitant ALL therapy, and (ii) there was no relation between IVZ plasma concentration and hepatic toxicity. Thus, in clinical practice IVZ may not require TDM.

Transhepatic absorption and biliary excretion of insulin

1987 ◽  
Vol 65 (9) ◽  
pp. 1982-1987 ◽  
Author(s):  
Walter Zingg ◽  
Aron M. Rappaport ◽  
Bernard S. Leibel
Keyword(s):  
Intravenous Administration ◽  
Biliary Excretion ◽  
Venous Blood ◽  
Intraperitoneal Administration ◽  
Liver Cells ◽  
Insulin Concentration ◽  
Secretory Process ◽  
Insulin Administration ◽  
Hepatic Cells ◽  
Liver Surface

The application of insulin to the liver in rats is followed by an increase of the insulin concentration in the bile. The pathway of insulin from the liver surface to the bile may include a secretory process by the hepatic cells, or it may bypass the hepatic cells, using direct anatomical pathways from blood and lymph to bile. The concentration of insulin in arterial and venous blood, in lymph, and in bile was measured following application of insulin to the liver surface and following peritoneal or intravenous administration. The results confirm that insulin is absorbed from the surface of the liver, but the glucose modulating effect was less effective than after intravenous administration. The insulin concentration in bile was increased after insulin administration by all routes, with the highest and most prolonged increases found after intraperitoneal administration. The results suggest that following transhepatic and intravenous administration, insulin reaches the bile without passing through the liver cells.

scholarly journals Analysis of free and protein-bound nitrotyrosine in human plasma by a gas chromatography/mass spectrometry method that avoids nitration artifacts

2000 ◽  
Vol 345 (3) ◽  
pp. 453-458 ◽  
Author(s):  
Matthew T. FROST ◽  
Barry HALLIWELL ◽  
Kevin P. MOORE
Keyword(s):  
Reactive Nitrogen Species ◽  
Plasma Proteins ◽  
Biological Fluids ◽  
Plasma Concentrations ◽  
Normal Subjects ◽  
Gas Chromatography Mass Spectrometry ◽  
Highly Sensitive ◽  
Acidic Conditions ◽  
First Time

Measurement of nitrotyrosine in biological fluids and tissues is increasingly being used to monitor the production of reactive nitrogen species in vivo. The detection of nitrotyrosine in vivo has been reported with the use of a variety of methods including immunoassay, HPLC and GLC/MS. The validity of HPLC and immunoassays have been questioned with regard to their selectivity and sensitivity limits. In principle, the measurement of nitrotyrosine by GLC/MS permits a highly specific, highly sensitive and fully quantitative assay. The nitration of tyrosine under acidic conditions in the presence of nitrite is well documented. Derivatization for the full quantification of nitrotyrosine by using GLC/MS can lead to the artifactual nitration of tyrosine if performed under acidic conditions in the presence of nitrite. We describe a novel alkaline method for the hydrolysis and derivatization of nitrotyrosine and tyrosine, and demonstrate its applicability to the measurement of plasma concentrations of both free and protein-bound nitrotyrosine and tyrosine. A detection limit of 1 pg for nitrotyrosine and 100 pg for tyrosine has been achieved. Our method allows, for the first time, the analysis of free and protein-bound nitrotyrosine and tyrosine in biological samples. The plasma concentrations (means±S.E.M.) of free tyrosine and nitrotyrosine in eight normal subjects were 12±0.6 μg/ml and 14±0.7 ng/ml respectively. Plasma proteins contained tyrosine and nitrotyrosine at 60.7±1.7 μg/mg and 2.7±0.4 ng/mg respectively.

scholarly journals Multiplicity of Hepatic Excretory Mechanisms for Organic Anions

1969 ◽  
Vol 53 (2) ◽  
pp. 238-247 ◽  
Author(s):  
Seymour Alpert ◽  
Michael Mosher ◽  
Alan Shanske ◽  
Irwin M. Arias
Keyword(s):  
Biliary Excretion ◽  
Organic Anion ◽  
Organic Anions ◽  
Bile Pigment ◽  
Johnson Syndrome ◽  
One Step

Previous studies based upon competition between different organic anions for biliary excretion in vivo have suggested that all organic anions share a common hepatic secretory mechanism. Corriedale sheep with an inherited defect in organic anion excretion by the liver were used to study this problem directly without the need for competition studies, the results of which are difficult to analyze. Maximal biliary excretion of sulfobromphthalein (BSP) in mutant Corriedale sheep was less than 7% of that observed in normal sheep whereas maximal biliary excretion of taurocholate, the major organic anion in sheep bile, was not different in mutant and normal sheep. Taurocholate infusion enhanced maximal hepatic excretion of BSP in normal but not in mutant sheep. These studies of an inheritable disorder which appears to be identical to the Dubin-Johnson syndrome in man, demonstrate that taurocholate excretion requires at least one step in biliary excretion which is not required by other organic anions such as bile pigment, porphyrins, drugs, and dyes.

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