Clearance In Man Research Articles

Lack of effect of dietary potassium on renal lithium clearance in man

The effects of alterations in dietary potassium (40, 80 and 160 mmol day-1) on endocrine status and on renal lithium clearance were assessed in 10 healthy subjects on a fixed sodium intake; measurements were made on the fifth day of each dietary regimen. Plasma aldosterone concentration was found to increase with potassium intake, whereas plasma renin activity and the plasma concentration of atrial natriuretic peptide did not change significantly. Neither absolute lithium clearance nor fractional lithium excretion was affected measurably by changes in dietary potassium, suggesting that provided the potassium intake remains within the normal range it is unnecessary to control this factor during lithium clearance studies in man.

Acute effects of thiazides, with and without carbonic anhydrase inhibiting activity, on lithium and free water clearance in man.

1. The acute effects of chlorothiazide and bendroflumethiazide on renal Li+ clearance (CLi) were studied in Na+-restricted healthy humans during maximum water diuresis. 2. Chlorothiazide, which has marked carbonic anhydrase inhibiting activity, increased CLi by about 25%. The concomitant rise in uric acid clearance, maximum urine flow and bicarbonate excretion suggests that this drug suppressed proximal reabsorption through carbonic anhydrase inhibition, which would also explain the observed fall in glomerular filtration rate (increased glomerulotubular feedback activity). 3. Bendroflumethiazide, which lacks carbonic anhydrase inhibiting activity, did not affect CLi or any of the other above-mentioned variables. 4. It is concluded from the lack of an effect of bendroflumethiazide on CLi that Li+ is not reabsorbed in thiazide-sensitive segments of the human distal nephron. The rise in CLi after chlorothiazide is most likely due to suppressed Li+ reabsorption in the proximal tubules resulting from carbonic anhydrase inhibition. 5. The results of this study are compatible with the concept that CLi is an index of Na+ and water delivery from the proximal tubules in humans.

The effect of age and frailty upon acetanilide clearance in man.

Six healthy young subjects (aged 23-32 years), six healthy elderly subjects (over 60 years) and six hospitalized long-stay geriatric subjects over 60 years received single oral doses of acetanilide. Acetanilide clearance was similar in the fit and frail elderly subjects at 26.4 +/- 2.5 and 26.3 +/- 3.6 l/h and significantly lower (p less than 0.05) than in the young subjects at 39.0 +/- 1.9 l/h. Liver volumes, measured by ultrasound, were significantly less in the elderly than in the young subjects, whether expressed in absolute terms or per unit body weight (p less than 0.05). When acetanilide clearance was expressed per unit volume of liver, no change occurred with age or frailty. These results suggest that a reduced liver size may be an important contributor to the reduced elimination of capacity limited drugs in elderly man.

In vivo dynamics of luteinizing hormone secretion and clearance in man: assessment by deconvolution mechanics.

The dynamics of LH secretion and clearance were studied in vivo in eight healthy young men using a novel multiple parameter deconvolution procedure to resolve underlying secretion and clearance rates simultaneously from serial serum immunoactive LH concentrations. This deconvolution analysis disclosed random LH secretory bursts occurring at a mean (+/- SEM) interpulse interval of 72 +/- 5 min. The frequency of these secretory bursts was 6.9 +/- 0.6 episodes/8 h. Each resolved LH secretory event had an average half-duration of only 7.8 +/- 0.5 min, which was remarkably shorter than the LH concentration peak duration of 60 +/- 6 min. The maximal LH secretory rate achieved within a secretory burst averaged 0.40 +/- 0.05 mIU/min.mL (0.14 IU/min.L), which corresponded to a mass of LH released of 3.2 +/- 0.3 mIU/mL distribution vol (IU/L). By linear regression analysis, both the maximal rate and mass of LH released per secretory burst were positively correlated with the duration of the subsequent interpulse interval (P less than 0.001). In physiological experiments, the mass of LH released per secretory burst was increased by iv GnRH injections or primary gonadal failure, and decreased by sc administration of a selective GnRH antagonist (Nal,Glu-GnRH). The mean endogenous LH production rate calculated by deconvolution [180 +/- 40 mIU/min (0.18 IU/min)] was not different from a nominal value of 228 +/- 80 mIU/min (0.228 IU/min) extrapolated from earlier steady state LH infusions. Deconvolution estimated single phase half-times of endogenous LH disappearance of 87 +/- 8 min, were in general harmony with values of 44-106 min obtained previously in four LH-deficient men injected with purified LH. Moreover, creation of synthetic LH series using our deconvolution estimates yielded 24-h LH pulse profiles similar quantitatively and qualitatively to those in normal men. In summary, we applied a new multiple parameter deconvolution procedure to immunoactive LH pulse profiles to discern the nature of physiological LH secretory events and estimate endogenous LH disappearance rates. These studies in normal men have revealed that 1) LH secretory bursts occur every 72 min; their mean half-duration is 7.8 min; and 3.2 mIU/mL (3.2 IU/L) are released per secretory peak; 2) amplitudes of in vivo LH secretory bursts are augmented in primary gonadal failure and/or by exogenous GnRH injections and attenuated by a GnRH antagonist; 3) the duration of a postsecretory pause is proportional to the amplitude of the preceding LH secretory burst; and (4) 95% of total daily LH release occurs in only 5 h/day.(ABSTRACT TRUNCATED AT 400 WORDS)

Lithium clearance in man: effects of dietary salt intake, acute changes in extracellular fluid volume, amiloride and frusemide.

1. The effects of amiloride and frusemide on lithium clearance were studied during changes in dietary sodium chloride intake and during infusion of 0.9% NaCl in normal human volunteers. 2. Lithium and fractional lithium clearances were less on the low than on the high salt diet. Values for the medium salt diet were intermediate. Acute extracellular fluid volume expansion with 0.9% NaCl infusion and extracellular fluid volume contraction 3-4 h after intravenous frusemide caused lithium and fractional lithium clearances to increase and decrease respectively. 3. Amiloride caused small changes in lithium and fractional lithium clearances on a low salt diet, but was without effect when salt intake was medium or high. 4. Increases in lithium clearance occurred immediately after frusemide irrespective of dietary salt intake and in subjects infused with 0.9% NaCl. Only in salt-depleted subjects did frusemide cause a substantial increase in fractional lithium clearance. Changes induced under other circumstances were small. 5. It is concluded that the lithium clearance method for assessment of proximal tubule salt and water reabsorption can be used with some degree of confidence in certain circumstances (medium and high salt intake as well as in acute volume expansion) but may not be reliable when dietary salt intake is low.

Effect of oral administration of a new calcium channel blocking agent, bepridil on antipyrine clearance in man.

Effect of oral administration of a new calcium channel blocking agent, bepridil on antipyrine clearance in man.

Effects of Panax ginseng on blood alcohol clearance in man.

1. Fourteen healthy male volunteers were studied to assess the effects of Panax ginseng on blood alcohol clearance, utilizing each subject as his own control. 2. At 40 min after the last drink, the blood alcohol level in the test group receiving ginseng extract (3 g/65 kg body weight) along with alcohol (72 g/65 kg body weight) was about 35% lower than their control values. 3. When the blood alcohol level was compared on individual bases, alcohol concentrations in 10 out of 14 test subjects ranged from 32 to 51% lower than their control values. 4. These results demonstrate that P. ginseng extract enhances blood alcohol clearance in man.

Methodological problems in the use of indocyanine green to estimate hepatic blood flow and ICG clearance in man.

Liver blood flow (Q) is often measured by constant infusion of ICG (i), concentration measurements in an artery (A) and a hepatic vein (V): Q = (A-V)/A. Some authors use ICG clearance, Cl = i/A, as a measure of Q assuming complete hepatic extraction. During the infusion, the ICG concentration often increases. The importance of this for calculated values of Q and Cl was examined, and the use of Cl as a measure of Q was reevaluated. ICG was given as 0.06-0.20 mumol/min to 52 subjects with liver disease, and about 0.20 mumol/min to 86 subjects with no liver disease. ICG concentration increased steeply during the first 90 min after start of the infusion; thereafter the increment was constant as evaluated in successive 40-min periods in eleven 320-min studies (analysis of variance P greater than 0.5); on average, 6 +/- 1% per hour (+/- SD). Q was not time-dependent (P greater than 0.5). ICG clearance decreased significantly, on average 5 +/- 2% per hour (+/- SD). Hepatic extraction fraction, (A-V)/A, (measurement period 90-130 min) was 0.34 +/- 0.21 in liver patients (+/- SD) and 0.61 +/- 0.80 in controls. Cl and Q were positively correlated in both groups but with substantial scatter. Thus, not only is the calculated ICG clearance time-dependent but the extraction fraction is further so low and variable, that any use of ICG clearance as a measure of liver flow is not justified.

Blood urea content changes in man under hypokinesia.

It has been demonstrated that hypokinesia (diminished muscular activity) leads to an increase in blood urea content in man. Against this background the objective of this investigation was to determine blood urea content under hypokinesia (HK) on 17 physically healthy men aged 19-23 yr. They were divided into three groups: the 1st group (5 men) was examined under HK, the 2nd group (4 men) was studied during the background period (BGP) as well as in the readaptation period (RTP), and the 3rd group (8 men) was placed under ordinary conditions and served as control. For the simulation of the hypokinetic effect the men were kept under a rigorous bed rest regime for 16 days. Blood urea, blood creatinine, urine urea, and urine creatinine were measured. The results were processed statistically. The most pronounced increased urea content was observed in the men with an initial low concentration (3.3-4.2 mmole/liter). Variations in the urea concentration were analogous and manifested a reduction during the initial days and an elevation thereafter. Creatinine excretion and clearance were reduced uniformly and significantly during the initial 10 days of HK. It was concluded that diminished muscular activity induced an increase in urea content and a decrease in creatinine clearance in man.

Amiodarone reduces plasma warfarin clearance in man.

Amiodarone is an effective antiarrhythmic agent whose use is associated with several drug interactions one of which is potentiation of the action of warfarin. The mechanism of this interaction has hitherto been unclear. We examined possible mechanisms in eight patients. Total plasma warfarin clearance was found to be reduced by amiodarone. No change was detected in the binding of warfarin to plasma proteins. No relationship was found between plasma amiodarone concentrations and the change in warfarin clearance.

Plasma clearance of chylomicrons labeled with retinyl palmitate in healthy human subjects.

To estimate hepatic uptake of chylomicron remnants in humans, chylomicrons and intestinal very low density lipoproteins (VLDL) were endogenously labeled with retinyl esters, harvested by plasmapheresis, and pulse-injected into the donor 44 hr after plasmapheresis. Plasma decay of retinyl palmitate was measured in eight healthy volunteers. Retinyl palmitate plasma disappearance obeyed an apparent first order function in seven studies and, in one study, a biexponential function with the second, slow exponential accounting for only 13% of the retinyl palmitate plasma decay. The mean fractional removal of rate was 0.037 +/- 0.037 min-1 (mean +/- SD) in a one-compartment model. The apparent volume of distribution, Vd, was 109 +/- 25% of the estimated plasma volume. Plasma clearance of retinyl palmitate was 130 +/- 97 ml/min calculated as Vd x Ke. Mean T 1/2 was 29 +/- 16 min. Both in vitro and in vivo the retinyl palmitate remained largely within chylomicrons and intestinal VLDL. Only 4.3% was transferred from chylomicrons to other lipoprotein classes during in vitro incubation for 5 hr. After plasma was stored for 42 hr, 5% was transferred to higher density lipoproteins. During 12 hr after a test meal containing retinyl palmitate, only 6.4 +/- 1.5% of the retinyl palmitate absorbed was found in the LDL fraction and 3.1 +/- 3.8% in the d 1.063 g/ml lipoproteins. We conclude that retinyl palmitate is a useful marker for chylomicrons and their remnants in humans and that the plasma clearance of retinyl palmitate-labeled chylomicrons is probably an estimate of chylomicron remnant plasma clearance in man.

Dose and concentration dependent effect of ranitidine on procainamide disposition and renal clearance in man.

The pharmacokinetics of oral procainamide (1 g) were investigated in six healthy subjects during chronic dosing with ranitidine 150 mg twice daily, and in three of the subjects when ranitidine 750 mg was administered over 12 h. The procainamide area under the plasma concentration-time curve was significantly (PQ0.02) increased by ranitidine (27.761.5 vs 31.561.8 mg l-1 h) with a significant reduction in renal clearance (379632 vs 309630 ml/min, PQ0.02). There was no change in half-life. The N-acetylprocainamide (NAPA) area under the plasma concentration-time curve was also significantly (PQ0.02) elevated by ranitidine (8.661.2 vs 9.761.3 mg 1-1 h) due to a reduction in renal clearance from 187630 to 168628 ml/min. The larger dose of ranitidine produced greater alterations in the procainamide and NAPA pharmacokinetics. Ranitidine reduced the absorption of procainamide by 10% and by 24% at the higher dose level. Two-hourly renal clearance values of procainamide were significantly (PQ0.05) reduced in the 2 to 10 h period and for NAPA between 0 to 6 and 8 to 10 h. The larger ranitidine dose reduced the renal clearances of procainamide and NAPA over the control period at each 2-hourly time period. The reductions in renal clearance are most likely mediated by competition for the renal tubular cationic secretory pathway. Clinical implications arising from this study suggest a reduction in procainamide dosage may be necessary in a small, select number of patients with high plasma ranitidine concentrations, e.g., the elderly; furthermore, failure of therapeutic response for some drugs may be due to ranitidine-induced impaired gastrointestinal absorption.

Acute effect of inhaled salbutamol on mucociliary clearance in health and chronic bronchitis.

We investigated in a double-blind study the acute effect of the inhaled beta 2-adrenergic agent salbutamol on mucociliary clearance in man. Subjects were 20 patients with chronic bronchitis (10 receiving the drug and 10 placebo) and 6 healthy individuals (3 receiving the drug and 3 placebo). Mucociliary clearance was evaluated after inhalation of a pressurized 99mTc-labelled a albumin aerosol (median mass aerodynamic diameter 2.85 microns). Particle deposition and clearance was determined by external recording with a large-field gamma camera and dedicated computer, for three consecutive hours without moving the subject. After 1 h baseline clearance recording the subject was given either salbutamol (500 micrograms) or vehicle alone from a commercial pressurized nebulizer; recording was then continued for a further 2 h (test period). Both patients and normals treated with salbutamol showed a significant increase in the rate of clearance when compared with their respective control group receiving placebo. Clearance rates (percentage activity cleared per hour) from the lungs in the hour after salbutamol inhalation averaged 33.1% +/- 13.5 (SD) per hour, for patients (control 12.2% +/- 5.6 (SD) per hour, p less than 0.001) and 16.1% +/- 4.3 (SD) per hour for normals (control 7.8% +/- 2.0 (SD) per hour, (p less than 0.005). Significant differences were also found in clearance rate before and after salbutamol inhalation in both treated groups. Cough events did not produce any significant effect on average mucociliary clearance. However, visualization of serial computer images in individual patients showed that cough may generate appreciable upward, downward or even lung-to-lung movements of radioactive boli.

Interpretation of interspecies differences in the biodistribution of radioactive agents

The biodistribution of some radioactive agents is anomalous and unpredictable from one species to another. However, many agents follow a general pattern of rapid clearance from the blood and total body in small rodents, intermediate clearance in the dog and monkey and slower clearance in man. A major determinant of this interspecies difference is the shorter mean circulation time (blood volume/cardiac output) in smaller animals. To permit comparisons between mammals of varying size, many physiological and metabolic parameters, and stable drug effects have been expressed as power functions with exponents less than 1 (rather than linear functions) of body weight W, or body surface area. Frequency functions such as heart and respiratory rates have been correlated with negative power functions of body weight. The plasma clearances of chemotherapeutic agents in different species has been successfully normalized by altering the time dimension according to power functions of body weight. A similar procedure has been explored to normalize blood and total body clearances of various diagnostic radioactive agents in animals and man. Time equivalent units were derived from W/sup 33/ animal / W/sup 33/ man. The method failed, however for agents with a predominantly intracellular localization or undergoing active cellular transport (suchmore » as T1-201 or I-131 Hippuran). Nonetheless, this approach appears useful in distinguishing interspecies variability merely due to body size from interspecies metabolic variations.« less

Influence of plasma glucose and insulin concentration on plasma glucose clearance in man.

We examined the influence of plasma glucose concentration on whole-body glucose uptake and glucose clearance at two physiologic levels of hyperinsulinemia. Twelve healthy, young volunteers were divided into two groups (A and B); each subject participated in three studies. In group A, plasma insulin was raised and maintained by ∼100 μU/ml for 3 h, while plasma glucose concentration was clamped at hypoglycemic (60 ± 1 mg/dl), euglycemic (89 ± 1 mg/dl), or hyperglycemic (165 ± 3 mg/dl) levels. In group B, plasma insulin was raised by ∼50 μU/ml, while plasma glucose was clamped at 62 ± 1,86 ±2, or 143 ± 3 mg/dl for 3 h. At the higher insulin level (group A), glucose uptake rose from 5.2 ± 0.5 to 7.3 ± 0.6 to 12.2 ±1.0 mg/min· kg as plasma glucose was varied from low to high levels; glucose clearance fell slightly from 8.8 ± 1.0 to 7.8 ± 0.7 to 7.3 ± 0.6 ml/min·kg during the hypo-, eu-, and hyperglycemic clamps (P = NS). At the lower insulin level (group B), glucose uptake rose from 6.0 ± 1.2 to 8.1 ±1.7 mg/min·kg (P < 0.05) with increasing glucose levels, whereas glucose clearance fell significantly (P < 0.01) from 9.7 ± 1.8 to 5.6 ±1.1 ml/min·kg. When the data from both groups were analyzed together, insulin had a stimulatory effect on both glucose uptake and clearance. Elevation of the plasma glucose level had a similar stimulatory effect on glucose uptake (P < 0.001) but inhibited glucose clearance (P < 0.01). This inhibition, however, was modest (14% for the change from hypo- to euglycemia, and 16% for the change from eu- to hyperglycemia). We conclude that physiologic hyperglycemia exerts a modest inhibitory effect on glucose clearance, which is largely overcome at higher, yet still physiologic, plasma insulin levels (∼100 μU/ml).

Urine flow-dependence of theophylline renal clearance in man.

Theophylline renal clearance is highly dependent on urine flow rate and is neither concentration nor dose related. To examine the flow dependency, theophylline was administered in single doses (4.3 mg/kg to 8.6 mg/kg) to 14 volunteers. Seven of these volunteers participated in studies in which theophylline and metabolite concentrations were held constant at six different levels. Due to the diuretic effect of theophylline, its renal clearance contributed up to 70% of the time-averaged total clearance, dose/total area, in the first hour after a single dose. The contribution then dropped to 5% of the time-averaged total clearance when the normal urine flow rate was restored. As a consequence of extensive tubular reabsorption, the urine/plasma concentration ratio of theophylline varied with urine flow rate and approached the value of the unbound fraction in plasma. On assumption that the reabsorption is passive, a mathematical model was used to explain the urine flow dependence of reabsorption and, therefore, the renal clearance of theophylline.

Effects of propranolol and pindolol on plasma lignocaine clearance in man.

1 Steady state concentrations and clearance of lignocaine were determine in eight healthy volunteers during 360 min continuous lignocaine infusion (2 mg/min). Before the infusion propranolol (0.18 mg/kg i.v.), pindolol (0.023 mg/kg i.v.) or placebo were administered in a random double-blind, cross over design. 2 During the infusion of lignocaine heart rate, cardiac output and arterial blood pressure were measured every 60 min. 3 Propranolol decreased heart rate and cardiac output significantly by 10--20%, while pindolol or lignocaine did not change cardiac output or heart rate significantly. None of the drugs changed the arterial blood pressure. 4 Propranolol pretreatment decreased lignocaine significantly by 14.7% and the steady state concentration was increased by 22.5%. Pindolol produced no significant change in steady state concentration or clearance of lignocaine.

Effect of pregnenolone--16 alpha-carbonitrile (PCN) on bilirubin clearance in man.

Effect of pregnenolone--16 alpha-carbonitrile (PCN) on bilirubin clearance in man.

Comparison of Three Methods for Measuring Nasal Mucociliary Clearance in Man

Three techniques for studying nasal mucociliary clearance have been compared in 20 normal subjects, aged 19 to 26. Three different tracers used were deposited on the septum or the nasal floor. The transport rate of a 250 micron anion resin particle tagged with 99mTc was measured over a distance of 3.5 cm. This method was used as reference. The transport time of saccharin was measured when the subjects tasted its sweetness on swallowing. The transport time of 600 micron aluminium discs was measured by observing their arrival at the pharynx. For each method, duplicate measurements were carried out over a 24 hour period. Despite the large variations in the results from one day to the next, a significant negative correlation (r = -0.59, p less than 0.001) was observed between the transport rate of the radioactive particles and the transport time of the saccharin. The daily variations in nasal clearance for these two methods were also significantly correlated (r = -0.53, p less than 0.02). These results validate the suitability of the saccharin method as a simple screening test for detecting abnormally low values of nasal mucociliary clearance. In our group of 20 subjects, 5 were characterized by a low nasal mucociliary clearance, whichever method was used.

Adrenergic mechanisms of catecholamine action on glucose homeostasis in man

To assess the adrenergic mechanisms responsible for the effect of epinephrine on glucose production and glucose clearance in man, epinephrine (50 ng/kg/min) was infused in the presence and absence of alpha adrenergic (phentolamine) and beta adrenergic (propranolol) antagonists under conditions when plasma glucose, insulin, and glucagon levels were allowed to vary and when they were clamped by a concurrent infusion of glucose, somatostatin, and insulin. When plasma glucose, insulin, and glucagon were permitted to vary during beta adrenergic blockade, plasma glucose and glucose production increased, respectively, 32% and 42% less and plasma epinephrine concentrations were threefold greater than those during infusion of epinephrine alone; plasma insulin decreased during beta blockade but increased during infusion of epinephrine alone; glucose clearance was comparably suppressed in both instances. When alpha adrenergic blockade was superimposed on beta blockade, the increase in glucose production and the decrease in both plasma insulin and glucose clearance observed during infusion of epinephrine alone was virtually abolished. In contrast, when plasma glucose, insulin, and glucagon were clamped, beta adrenergic blockade completely prevented the suppression of glucose clearance by epinephrine and inhibited the stimulation of glucose production by epinephrine by 80% whereas alpha adrenergic blockade had no effect on either of these parameters. These results indicate that in man, epinephrine increases glucose production and decreases glucose clearance by both alpha and beta adrenergic actions. The alpha adrenergic effects could be accounted for by inhibition of insulin secretion. The mechanism for the beta adrenergic effects remains to be defined but may reflect a direct action of epinephrine on hepatic and peripheral tissues.