Component Of Clearance Research Articles

89Sr Therapy: Strontium plasma clearance in disseminated prostatic carcinoma

Strontium plasma clearance is an important factor determining the absorbed dose to metastases and bone marrow in patients receiving 89Sr radionuclide therapy for metastatic bone disease. Amongst male patients with disseminated prostatic carcinoma, the renal component of strontium clearance is frequently greatly reduced compared with values reported for healthy middle aged men. We report a study of renal and gut strontium plasma clearance, renal function, calcium urinary excretion, parathyroid function and extent of skeletal osteoblastic metastatic disease in patients referred for radiostrontium therapy for metastasised prostatic malignancy. The wide variation in net strontium clearance was principally due to variation in the renal component. Low values of strontium renal clearance were found to correlate with the elevation of serum PTH and nephrogenous cyclic AMP, which in turn correlated with extent of skeletal metastatic disease. This suggests that the osteosclerotic metastases characteristic of prostatic carcinoma induce secondary hyperparathyroidism due to the high avidity of the skeleton for calcium. The resulting reduction in strontium excretion may be beneficial to the objectives of radiostrontium therapy.

Influence of Adsorption to Carbon Black Particles on the Retention and Metabolic Activation of Benzo[a]Pyrene in Rat Lungs Following Inhalation Exposure or Intratracheal Instillation

AbstractThere is a need to define the influence of adsorption of organic compounds onto particles on the biological fate of these compounds when inhaled. In this study, rats were exposed by nose-only inhalation (2 h) to 2 mg/m3 or 20 mg/m3 of pure [14C]BaP or [14C]BaP adsorbed onto carbon black particles at 0.2 mg/m3, 2.0 mg/m3, or 20 mg/m3 (total mass concentration ≃ 100 mg/m3). In separate studies, rats were intratracheally instilled with amounts of pure [14C]BaP and [14C]BaP on carbon black that were similar to those deposited in lungs by inhalation. In all cases, clearance of 14C from lungs had a rapid short-term component and a slower long-term component of clearance. As a percentage of the calculated initial lung deposition after inhalation or instillation, the long-term retention of 14C was similar for all amounts of pure [14C]BaP used and also similar for both methods of administration. The long-term lung retention of 14C as a percentage of the initial lung deposition was increased 16–60 times as ...

Investigations on Insulin Kinetics

Insulin is secreted into the portal vein by the pancreas at varying rates. A fraction of this newly secreted insulin is taken up by the liver on a first pass basis. The remainder is distributed throughout the peripheral tissue and removed at many sites in the system. The insulin secretion rate is calculated by deconvolution from C-peptide concentrations, a peptide that is co-secreted with insulin on an equimolar basis. This calculation has been experimentally validated. Peripheral insulin kinetics are handled in a general way by using insulin tracers and compartmental modelling of Insulin dynamics. The post-hepatic rate of insulin appearance can be calculated under general circumstances within 10%. The hepatic extraction of insulin can be calculated (i) by arteriovenous differences across the splanchnic bed. (ii) As the difference between the rate of insulin secretion and its peripheral appearance or (ili) the fractional extraction can be determined continuously as the peripheral appearance of a second tracer administered in the splanchnic bed. It is concluded that, in dogs, as portal insulin levels increase to 600uU/ml, the hepatic extraction of insulin falls by approximately 50% and the fractional disappearance rate of insulin by two thirds. This suggests that insulin removal by the liver is the principal component of the metabolic clearance of insulin and that it may vary under physiological circumstances. This paper therefore provides approaches, both experimental and quantitative for determining the major parameters Involved in insulin kinetics — its rate of secretion and removal by the liver, when these are varying.

An exact analysis for a solute transport, due to simultaneous dialysis and ultrafiltration, in a hollow-fibre artificial kidney

Transport of a uremic solute effected by a combined dialysis and ultrafiltration procedure in a hollow-fibre artificial kidney, is investigated theoretically under standard assumptions. An exact analytical solution for the concentration profile in a blood channel is obtained by using the method of separation of variables. The necessary requirement that the solution must tend to that of pure dialysis, in the limit ultrafiltration tending to zero, is fulfilled. Exact analytical expressions are derived for the eigenconstants of the solution. In using the solution, the solute clearance is emphasized. Diffusive and ultrafiltration components of the solute clearance are defined and studied. The combined procedure is examined for middle versus small molecules and for polyacrylonitrile versus cuprophan hollow-fibres.

Alterations in particle accumulation and clearance in lungs of rats chronically exposed to diesel exhaust

F344 rats were chronically exposed to diesel exhaust at target soot concentrations of 0 (control, C), 0.35 (low, L), 3.5 (medium, M), and 7.0 (high, H) mg/m 3. Accumulated lung burdens of diesel soot were measured after 6, 12, 18, and 24 months of exposure. Parallel measurements of particle deposition and clearance were made to provide insight into the mechanisms of particle accumulation in lungs. The fractional deposition of inhaled 67Ga 2O 3 particles after 6, 12, 18, and 24 months of exposure and of inhaled 134Cs-fused aluminosilicate particles after 24 months were similar for all groups. Progressive increases in lung burdens of soot particles were observed in M and H exposed rats, reaching levels of 11.5 ± 0.5 and 20.5 ± 0.8 mg/lung ( x ± SE ), respectively, after 24 months. Rats in the L group had smaller relative increases in lung burden, reaching levels of 0.60 ± 0.02 mg/lung after 24 months. Tracheal mucociliary clearance measurements, using 99mTc-macroaggregated albumin deposited in the trachea, showed no changes at any time. There were statistically significant increases in clearance half-times of inhaled radiolabeled particles of 67Ga 2O 3 as early as 6 months at the H level and 18 months at the M level; no significant changes were seen at the L level. Rats inhaled fused aluminosilicate particles labeled with 134Cs after 24 months of diesel exhaust exposure to measure long-term components of pulmonary clearance. The long-term clearance half-times were 79 ± 5, 81 ± 5, 264 ± 50, and 240 ± 50 days ( x ± SE ) for the C, L, M, and H groups, respectively. Differences were significant between the C and both the M and H exposure groups ( p < 0.01). Lung burdens of diesel soot were more than expected at the H and M levels and were also associated with impaired particle clearance while smaller responses were observed in both burdens and clearance at the L level.

Lung clearance and disposition of 63Ni in F344/N rats after intratracheal instillation of nickel sulfate solutions

Epidemiology studies have indicated increased incidences of respiratory tract and renal cancer in nickel refinery workers. Since the most likely route of exposure to nickel in the workplace is via the respiratory tract, the objectives of the experiments described here were to determine the retention pattern of Ni in the lungs, identify the target organs for Ni absorbed from the respiratory tract, and determine rates for excretion of Ni. Male and female F344 rats were given 17, 190, or 1800 nmoles Ni (as a nickel sulfate solution) in saline, containing trace amounts of 63Ni, by intratracheal instillation. Urine and feces were collected, and rats were necropsied at predetermined times up to 96 hr after instillation. At all times, lungs, trachea, larynx, kidney, and urinary bladder contained the highest concentrations of Ni as determined by liquid scintillation spectrometry. Urine was the major route for excretion of Ni, accounting for 50% of the dose after instillation of 17 or 190 nmoles Ni, and 80% of the dose after instillation of 1800 nmoles Ni. The half-time for urinary excretion of Ni increased from 4.6 hr at the highest dose to 23 hr at the lowest dose used. Fecal excretion accounted for 30% (17- and 190-nmole doses) or 13% (1800 nmoles) of the initial dose. Of the Ni remaining in the body at the end of 96 hr, over 50% was in the lungs. The long-term half-time for clearance of Ni from the lungs ranged from 21 hr at the highest dose to 36 hr at the lowest dose instilled. As the amount of instilled Ni decreased, the fraction of the instilled Ni associated with the long-term clearance component increased (from 24% at the highest dose to 40% at the lowest dose). Results suggest that, over the range of doses studied, both pulmonary clearance of Ni and routes for excretion of Ni were dependent on the instilled dose.

An exact analysis for a solute transport, due to simultaneous dialysis and ultrafiltration, in a hollow-fibre artificial kidney

Transport of a uremic solute effected by a combined dialysis and ultrafiltration procedure in a hollow-fibre artificial kidney, is investigated theoretically under standard assumptions. An exact analytical solution for the concentration profile in a blood channel is obtained by using the method of separation of variables. The necessary requirement that the solution must tend to that of pure dialysis, in the limit ultrafiltration tending to zero, is fulfilled. Exact analytical expressions are derived for the eigenconstants of the solution. In using the solution, the solute clearance is emphasized. Diffusive and ultrafiltration components of the solute clearance are defined and studied. The combined procedure is examined for middle versus small molecules and for polyacrylonitrile versus cuprophan hollow-fibres.

Observations on dermal blood flow as reflected by Technetium-99m pertechnetate clearance

Skin blood flow as reflected by the clearance rate of intradermal injections of Technetium-99m (99mTc) was studied in the skin of human volunteers and in a variety of clinical situations. In volunteers comparisons between the effect on clearance following intradermal injections of either lignocaine or lignocaine/adrenaline showed that the latter resulted in a dramatic reduction in the clearance rate of the technetium isotope and that such clearance curves exhibited no fast component. Clinical studies in grossly ischaemic skin revealed a similar absence of the fast component of isotope clearance and this was also the case for healed split thickness skin grafts. The dermal isotope clearance was also used in pedicle skin flaps both before and after clamping the axial pedicle in order to derive clearance ratios which would reflect the degree of neovascularisation to the flap.These preliminary observations suggest that the technique is safe, and easy to use in many clinical circumstances. We consider that it offers a valuable method by which changes in dermal blood flow may be quantified, when simultaneous control areas of isotope clearance are also studied. Suggestions are made for further avenues of study.

Esophageal emptying and acid neutralization in patients with symptoms of esophageal reflux.

Clearance of refluxed acid from the distal esophagus is due to bolus emptying and salivary neutralization of acid. We compared results of 24-hour pH monitoring with acid clearance tests (ACT) and radioisotope swallows (RIS) in 26 symptomatic patients to determine which of the components of acid clearance is better correlated with gastroesophageal acid reflux (GER). Seven of eight patients with GER had delayed esophageal emptying on RIS. Abnormal salivary clearance of acid was present in nine of 18 patients without GER, accounting for a high false-positive rate of ACT. Delayed esophageal bolus emptying, not deficient acid neutralization by saliva, is the predominant component of abnormal acid clearance in patients with GER. RIS is superior to ACT as part of the evaluation of reflux symptoms, and may prove to be a valuable screening test for this condition.

Influence of Cimetidine on Bupivacaine Disposition in Rat and Monkey

Recent reports have appeared describing a cimetidine-induced alteration in either the input or disposition function for many drugs. The total clearance component of the disposition function is the primary perturbation. In the present investigation, the influence of cimetidine on bupivacaine disposition was studied, using in vitro and in vivo models. Since the extraction ratio for bupivacaine is low, total clearance follows the capacity-limited theory. Hence, the influence of cimetidine on the intrinsic clearance of bupivacaine was assessed using microsome and hepatocyte models. Results for both systems are in excellent agreement and indicate a noncompetitive inhibition. Additionally, the influence of cimetidine on the protein-binding profile of bupivacaine was determined. In the presence of cimetidine, the these findings was assessed in vivo in rhesus monkeys. co-administration of cimetidine resulted in an increase in the volume of distribution at steady state and no change in the total clearance of bupivacaine.

In vivo administration of purified human interleukin 2. I. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2.

A total of 12 patients with cancer or the acquired immunodeficiency syndrome have been treated with Jurkat-derived purified human interleukin 2 (IL 2). The toxicity was dose-related and consisted primarily of fever, chills, malaise, and mild reversible hepatic dysfunction. No evidence of clinical efficacy was seen when IL 2 was administered at doses of up to 2000 micrograms by bolus or continuous infusion once a week for 4 wk. No significant chronic immunologic effects (changes in mitogen responsiveness of induction of cytotoxic cells) were demonstrated. IL 2 was measured in the serum of patients, and a half-life of approximately 5 to 7 min was demonstrated with a second component of clearance of 30 to 120 min. Heating the serum at 56 degrees C for 30 min allowed for detection of smaller quantities of IL 2 by removing a serum inhibitor whose effect was seen at dilutions of up to 1/80 in our biologic assay. Sustained levels of IL 2 could be maintained by continuous infusion. Acute effects of IL 2 administration included a rapid decrease in peripheral mononuclear cells with a shift to cells of macrophage lineage and a rapid decrease in total T lymphocytes and T lymphocyte subsets. IL 2 responsiveness of peripheral mononuclear cells decreased within 15 min of IL 2 administration, with a concurrent decrease in the ability to generate lymphokine-activated killer cells. These changes did not recover until 48 hr after IL 2 administration. A rise in serum ACTH and cortisol levels was seen after the administration of 1 to 2 mg of IL 2. Future studies will evaluate the role of larger quantities of recombinant IL 2 given alone or in conjunction with in vitro-generated lymphokine-activated killer cells.

Lung retention and metabolic fate of inhaled benzo( a)pyrene associated with diesel exhaust particles

Polycyclic aromatic hydrocarbons (PAHs) are a class of compounds considered to have human carcinogenic potential and have been found associated with many respirable, environmental particle pollutants. The effect of these ultrafine, insoluble, carrier particles on the lung retention and metabolic fate of inhaled PAHs was investigated with a radiolabeled model PAH, [ 3H]benzo( a)pyrene ( 3H-BaP). Fischer-344 rats were exposed (30 min) by nose-only inhalation to 3H-BaP adsorbed (∼0.1% by mass) onto diesel engine exhaust particles. These aerosols were generated in a dynamic aerosol generation system by vapor condensation methods. The total mass concentration of these aerosols was 4–6 μg/liter of air with a mass median diameter of 0.14 μm. Lung clearance of the inhaled particle-associated 3H radioactivity occurred in two phases. The initially rapid clearance of this inhaled radiolabel had a half-time of less than 1 hr. The second, long-term component of lung clearance had a half-time of 18 ± 2 days and represented 50 ± 2% of the 3H radioactivity that had initially deposited in lungs. In contrast, previous inhalation studies with a pure 3H-BaP aerosol showed that >99% of the 3H radioactivity deposited in lungs was cleared within 2 hr after exposure (Sun et al., Toxicol. Appl. Pharmacol. 65, 231–244, 1982). By HPLC analysis, the majority of diesel soot-associated 3H radioactivity retained in lungs was BaP (65–76%) with smaller amounts of BaP-phenol (13–17%) and BaP-quinone (5–18%) metabolites also being detected. No other metabolites of BaP were detected in lungs of exposed rats. Tissue distribution and excretion patterns of 3H radioactivity were qualitatively similar to previous inhalation studies with 3H-BaP coated Ga 2O 3 aerosols (Sun et al., 1982). These findings suggest that inhaled PAHs may be retained in lungs for a greater period of time when these compounds are associated with diesel engine exhaust particles. In addition, these compounds retained in lungs can be metabolized in lungs. These results may have significant implications for the health risks that may be involved with human exposure to particle-associated organic pollutants.

Effect of heparin on the in vivo release and clearance of human platelet factor 4

Intravenous injection of heparin (100 U/kg) into normal volunteers resulted in an increase of platelet factor 4 (PF4) level in platelet- poor plasma from a mean value of 18.1 +/- 6.6 ng/ml before the injection to 257.9 +/- 68.3 ng/ml at 5 min after injection. PF4 antigen isolated from “postheparin plasma” by adsorption on heparin-agarose and elution with 2.0 M NaCl and “authentic PF4” isolated from human platelets showed identical patterns of migration as determined by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Material released by washed human platelets was injected intravenously into rats. The clearance of PF4 followed a biphasic exponential pattern. The half-lives (T1/2) for the fast and slow components for control rats were 1.2 and 17.1 min. Heparin significantly extended the half-life of human PF4 in rat circulation. The clearance of PF4 injected together with heparin followed a single component model with a half-life of 27.6 min. Administration of heparin to rats that had been previously injected with human platelet releasate resulted in a 30-fold increase of plasma PF4 level in their circulation. The clearance of PF4 from the circulation of these rats (T1/2 = 45 min) fitted a single component model. We propose that PF4 is originally secreted by platelets into circulation and subsequently bound reversibly to vascular sites from which it can be released back into the circulation by heparin. The fast component of PF4 clearance that is abolished by heparin may reflect binding of this protein to the endothelial cells.

Effect of Heparin on the In Vivo Release and Clearance of Human Platelet Factor 4

Intravenous injection of heparin (100 U/kg) into normal volunteers resulted in an increase of platelet factor 4 (PF4) level in platelet-poor plasma from a mean value of 18.1 +/- 6.6 ng/ml before the injection to 257.9 +/- 68.3 ng/ml at 5 min after injection. PF4 antigen isolated from "postheparin plasma" by adsorption on heparin-agarose and elution with 2.0 M NaCl and "authentic PF4" isolated from human platelets showed identical patterns of migration as determined by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Material released by washed human platelets was injected intravenously into rats. The clearance of PF4 followed a biphasic exponential pattern. The half-lives (T1/2) for the fast and slow components for control rats were 1.2 and 17.1 min. Heparin significantly extended the half-life of human PF4 in rat circulation. The clearance of PF4 injected together with heparin followed a single component model with a half-life of 27.6 min. Administration of heparin to rats that had been previously injected with human platelet releasate resulted in a 30-fold increase of plasma PF4 level in their circulation. The clearance of PF4 from the circulation of these rats (T1/2 = 45 min) fitted a single component model. We propose that PF4 is originally secreted by platelets into circulation and subsequently bound reversibly to vascular sites from which it can be released back into the circulation by heparin. The fast component of PF4 clearance that is abolished by heparin may reflect binding of this protein to the endothelial cells.

Clearance of circulating DNA-anti-DNA immune complexes in mice.

DNA-anti-DNA immune complexes, produced from single-stranded DNA and IgG from a patient with systemic lupus erythematosus were cleared from the circulation of normal mice extremely rapidly, at a rate similar to the clearance of DNA alone. The initial clearance of these complexes was more rapid than the clearance of aggregated IgG, a surrogate immune complex containing a comparable number of IgG molecules, suggesting that the antigen (DNA) in the complexes significantly altered the clearance kinetics of the complexes. Analysis of the late clearance component of these complexes showed that anti-DNA is released back into the circulation after initial removal, and is then cleared at a rate similar to monomeric IgG. Whether this anti-DNA represents free antibody, or antibody bound to small nuclease digested DNA fragments, awaits further study.

Kinetics of positron emitters in vivo characterized with a beta probe.

To facilitate characterization of regional myocardial kinetics of positron-emitting tracers in vivo without distortion by activity outside the region of interest, a probe was developed and evaluated for monitoring radioactivity by detection of positrons themselves. These particles (beta particles) have a maximal range in tissue of only few millimeters rather than the larger range of gamma photons emitted as a result of positron annihiliation. Regional myocardial time-activity curves were determined in open-chest dogs after intracoronary injection of 0.5-1.5 mCi [15O]H2O, a tracer used for measurement of myocardial blood flow, or 6.0-8.0 mCi [11C]palmitate, a tracer used for noninvasive assessment of myocardial metabolism. Time-activity curves after [11C]palmitate injection clearly delineated specific components of myocardial tracer clearance previously identified in vitro in isolated perfused hearts. Myocardial washout of [15O]H2O was monoexponential for more than 2 min without distortion induced by recirculating tracer in ventricular blood. Reproducibility of measured tracer clearance rates during monoexponential clearance was high based on duplicate determinations for both tracers. The beta-detector probe developed overcomes several intrinsic limitations of gamma-probe systems or well counting of serial myocardial biopsies for studies of positron-emitting tracers in vivo and should facilitate assessment of factors of influencing tracer kinetics in vivo relevant to positron-emission tomography.

Characterization of the renal handling of vasopressin in the dog by stop-flow analysis.

The stop-flow technique has been used to characterize the renal handling of vasopressin in the anesthetized dog. To facilitate the measurement of vasopressin in small urine samples by a specific RIA, the plasma vasopressin concentration was elevated by the iv infusion of arginine vasopressin. Under control conditions, the urinary clearance of vasopressin did not differ significantly from the glomerular filtration rate. The data obtained with the stop-flow technique indicate that vasopressin was reabsorbed from or degraded in the proximal nephron and secreted into the distal nephron. Thus, vasopressin excreted in the final urine is the result of glomerular filtration (which is limited to the extent that vasopressin is bound to plasma proteins), proximal reabsorption or degradation of filtered vasopressin, and distal secretion of vasopressin. It is likely that the tubular secretion of vasopressin is an important component of the renal organ clearance of this hormone.

The excretion of selenium in bile and urine of steers: the influence of form and amount of Se salt

1. The excretion of 75Se and stable Se in bile and urine was measured in four steers during 6 h after intravenous injections of 75Se as either selenite or selenate containing either 5 or 5000 microgram carrier Se. 2. When 5000 microgram Se were given, the rate of urinary excretion and plasma clearance of 75SE was similar for both salts. Approximately 23% was excreted in urine and plasma clearance was triexponential, the mean half-life (t 1/2) of the successive components, alpha, beta, and gamma, being 2.3, 15-2 and 465 min respectively. The amount of 75Se excreted in bile was small; 1.94% of the 75SeO3(2-) and 0.86% of the 75SeO4(2-) dose. 3. When 5 microgram Se were given the plasma clearance of 75Se was initially biexponential but the entry of 75Se-labelled protein from the liver caused an increase in plasma radioactivity after 30-40 min. The effect was most marked after 5 microgram 75SeO3(2-) when plasma 75Se radioactivity returned to 69% of the activity present at 2 min. Values for t 1/2 of the two components of clearance for 75SEO4(2-) were respectively alpha 2.6 and 2.5 min, and beta 15.9 and 36.6 min. Similar amounts of 75Se appeared in bile (0.2% of the dose) after injection of either salt but much less 75Se was excreted in urine after 75SeO3(2-) (6%) than after 75SeO4(2-) (17%). 4. At low dosage rates (5 microgram) Se is more readily incorporated into tissues from SeO3(2-) than from SeO4(2-).

Cortical blood flow: thermal diffusion vs isotope clearance.

A thermal diffusion flow probe incorporating a Peltier stack has been found to give a quantitative dynamic assessment of cortical blood flow in both the laboratory and clinical settings. Further calibration characteristics of the probe were evaluated by correlation with the fast component of Xe133 clearance in cats. The correlation has some linear characteristics but is better defined by the equation: CBFp = phi(1/delta V - 1/delta Vo) Where CBFp is flow in ml/100 g/min, delta V is the voltage difference of the thermocouples, and delta Vo is the voltage difference of the thermocouples with no flow, which was 342.8 +/- 12.9 microv. Phi describes the characteristics of the probe and was determined to be 52,431.2 +/- 4796.3. The average deviation of the calculated curve from the experimental data points was +/- 6.3. The calculated phi differed markedly from the mean when Xe133 fast component flows were less than 35 ml/100 g/min. This is evidence that CBF as measured by Xe133 clearance analyzed by the bicompartmental technique loses accuracy at lower flows. The thermal diffusion flow probe is a good device for evaluation of flow in acute ischemia models since it can delineate abrupt flow variations. Theoretically the flow probe can accurately measure flow at ischemic levels.

Metabolism and pharmacokinetics of TRH and an analogue with enhanced neuropharmacological potency

The biological stability and pharmacokinetics of TRH and a 3,3-dimethylprolineamide analogue have been compared. Studies in-vitro showed the analogue to be almost completely resistant to plasma or tissue homogenates of rat, dog and man, in contrast, TRH was rapidly degraded. In rats, the total plasma clearance of TRH was greater than for the analogue principally because of an 8-fold higher metabolic component of clearance. In both rat and dog the renal clearance of the peptides approximated to the rate of glomerular filtration. It is concluded that biological stability increases bioavailability both systemically and centrally and that this goes some way to explaining the increased neuropharmacological potency of the analogue.