Relation between renal and hepatic excretion in drugs. VIII. Influence of triiodothyronine on maturation of phenol red excretion in rats.

Experiments were performed on 10-, 20-, and 55-day-old female rats. Administration of triiodothyronine (T3; 10 or 20 micrograms/100 g b.wt. for 3 days, once daily) was followed by a significant increase in renal phenol red excretion in 20-day-old and older rats. In 10-day-old rats there was no stimulatory effect of T3 on renal excretion of the dye. On the other hand, biliary excretion of phenol red was significantly diminished in all age groups. Surprisingly, in nephrectomized rats there was a significant increase in hepatic dye excretion in 20- and 55-day-old rats after T3. This increase in transport capacity via liver was connected with a distinct rise of bile flow. In experiments on tissue slices phenol red accumulation was investigated at different medium concentrations. In renal cortical slices there was no significant influence of T3 on specific accumulation of phenol red per 1 g organ wet weight, whereas aerobic accumulation of the dye seems to be diminished in liver tissue after T3 treatment. But in all age groups kidney weight increased significantly. Calculation of total accumulation (= specific accumulation x organ wet weight) resulted in a significantly enhanced renal transport capacity for phenol red in all age groups. In contrast, total hepatic accumulation was reduced independently of age.

Relation between renal and hepatic excretion of drugs: IX. Acceleration of phenol red excretion via kidney and liver in rats of different ages by dexamethasone treatment.

Experiments were performed on 10-, 20-, and 55-day-old female rats. After treatment with dexamethasone (60 or 80 micrograms/100 g b.wt. for 3 days, once daily) there is a significant increase in renal phenol red excretion only in 10-day-old rats. In contrast, the stimulatory effect of dexamethasone treatment on the hepatic excretion of this dye occurs exclusively in mature, 55-day-old rats. After repeated administration of this hormone in nephrectomized rats there is an increase of hepatic phenol red excretion, and maximal transport capacity increases from 6-8 to 12 mg/100g b.wt. X hour. In renal cortical slices there is no significant influence of dexamethasone on phenol red accumulation in vitro, whereas accumulation of the dye in liver tissue seems to be diminished. In rats of all groups kidney and liver weights increased significantly after dexamethasone treatment. Calculation of total accumulation capacity (= accumulation per 1 g X organ wet weight) also results in unchanged accumulation capacity in the kidney, but transported phenol red amounts in the liver are distinctly diminished. This is in contrast to the in vivo findings. Possible reasons are discussed.

Pharmacokinetics of phenolsulfonphthalein in horse and pony mares.

Pharmacokinetics of phenolsulfonphthalein (PSP) in horse and pony mares was determined after injection of 1 mg/kg of body weight, IV. A plasma PSP concentration vs time curve was described adequately in horses and ponies by an open, 2-compartment model. There were significant differences in the elimination phase parameters, apparent volume of distribution at steady state, and apparent volume of distribution of horses and ponies. The harmonic mean elimination half-life of PSP in horses was significantly longer (P less than 0.001) than that in the ponies (16.4 and 10.0 minutes, respectively). The mean plasma clearance of PSP in horses was significantly (P less than 0.05) less than that in ponies (0.00554 and 0.00701 L/min/kg, respectively). There was no difference between horses and ponies in the metabolic clearance of PSP. The fraction of the administered dose of PSP excreted in the urine in the first 15 minutes was not significantly different between horses and ponies.

Physiologically based pharmacokinetic model for the renal clearance of phenolsulfonphthalein and the interaction with probenecid and salicyluric acid in the dog.

Plasma kinetics and renal excretion of intravenous phenolsulfonphthalein (PSP, 1.0 g), with and without concomitant administration of probenecid or salicyluric acid (SUA), were studied in the Beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by probenecid and SUA. A physiologically based kidney model was developed that incorporates the functional characteristics of the kidney that determine the excretion of PSP, i.e., renal plasma flow, urine flow, nonlinear protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. The interaction with probenecid and SUA could be adequately described with the model by inhibition of the carrier-mediated uptake of PSP into the proximal tubular cells. However, both compounds clearly differed in their inhibitory action. Whereas probenecid showed simple competitive inhibition, for SUA a considerably more complex interaction (two-site competitive system) had to be taken into consideration. Especially in the interaction experiments, only satisfactory fits to the model were obtained when secretion was assumed to be dependent on unbound PSP concentrations. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of PSP within the proximal tubular cells, which was clearly diminished in presence of probenecid or SUA. The predicted accumulation ratios were in good agreement with previous studies.

Relation between renal and hepatic excretion of drugs: I. Phenol red in comparison with p-aminohippurate and indocyanine green.

Phenol red is a suitable compound for the simultaneous assay of renal and hepatic excretion in the rat. Its elimination has been compared with those of p-aminohippurate (PAH) and indocyanine green (ICG) which are eliminated nearly exclusively via kidneys or liver, respectively. The interruption of one elimination route one day before the experiment, that means bile duct ligation (DL) in the case of ICG or bilateral nephrectomy (NX) in the case of PAH are followed by a slight increase in the elimination via the alternative pathway, but no effective compensation occurs. On the other hand, the renal excretion of phenol red is significantly increased after DL only following administration of high doses. This intensification is caused by an increase in the unbound amount of phenol red depending on the plasma concentration and reflects an enhanced glomerular filtration fraction. The biliary excretion increases significantly after NX, but only after infusion of low doses. The maximal biliary secretion capacity cannot be exceeded following NX, either. The competitive inhibition of phenol red excretion by probenecid supports the findings of NX or DL experiments. An influence of the three test substances on arterial blood pressure has been excluded. The most important factors influencing the switch over from one to the other elimination route seem to be at least in the case of phenol red the amount of unbound substance, the influence of the administered dose on the glomerular filtration, and disturbances in the volume of distribution, e.g. the possible reduction of hepatic uptake after DL.

Relation between renal and hepatic excretion of drugs. II. Age-dependence of phenol red excretion in comparison with those of p-aminohippurate and indocyanine green.

The excretory functions of kidney and liver do not develop simultaneously during the maturation of an individual. Therefore age related differences in the relation between renal and hepatic drug excretion could be expected. In this study the excretion of p-aminohippurate (PAH) and indocyanine green (ICG) as model substances for nearly exclusive excretion via kidney or liver, respectively, have been compared with that of phenol red eliminated both via kidneys and liver (3:1). Experiments were performed on rats between the 10th and 105th days of life. For PAH and ICG the typical age courses of renal or hepatic excretion have been confirmed. Both urinary and biliary phenol red excretion show an influence of age, however, renal elimination reaches adult values as early as at the 20th day of life. Furthermore the age relation concerning compensation of the loss of kidney or liver excretory functions has been studied. Neither after nephrectomy (NX) nor after bile duct ligation (DL) the PAH or ICG elimination via the alternative pathway, respectively, were quantitatively increased. Thus a compensation of the interruption of the main elimination route does not occur in all ages. In contrast, phenol red excretion into urine and bile increases distinctly after DL or NX. This increase becomes even significant after administration of suitable doses of phenol red saturating transport capacities of liver or kidney. The compensation is first of all caused by passive pharmacokinetic changes. Active compensatory mechanisms have not been proved.

Renal secretion of phenolsulfonphthalein: analysis of its vectorial transport in normal and mutant analbuminemic rats.

Transtubular transport of many organic anions, such as p-aminohippuric acid and phenolsulfonphthalein (PSP), from plasma into urine is an important renal function. Most of these nephrophilic ligands strongly bind to albumin in the circulation. To investigate a possible function of plasma albumin in vectorial transport of these organic anions, plasma clearance and urinary excretion of PSP, on one hand, and its interaction with serum proteins, on the other, were studied in normal and mutant Nagase analbuminemic rats (NAR). Intravenously administered PSP rapidly disappeared from the circulation, followed by its urinary excretion in both NAR and normal rats. However, its plasma clearance was significantly larger in NAR (53.9 ml/min/kg body weight) than in normal animals (4.7 ml/min/kg body weight). Gel exclusion Sephadex G-100 chromatography and ultrafiltration analysis revealed that the PSP binding capacity of serum proteins was considerably lower in NAR than in normal rats; 32.0% and 12.5% of the ligand bound to NAR serum protein and 94.4% and 84.2% to normal rat serum protein (predominantly albumin) at 0.1 and 0.5 mmol/L ligand concentrations, respectively. Despite the greater PSP clearance in NAR, its urinary excretion was lower in NAR than in the normal animals; 20.9% +/- 2.5% and 46.0% +/- 12.6% of the administered dose appeared in NAR and normal rat urine, respectively, within 3 hours of administration. Injection of PSP with equimolar albumin resulted in a decrease in plasma clearance and an increase in urinary excretion of PSP in NAR; more than 31.4% +/- 3.3% of the injected dose appeared in the urine within 3 hours of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenolsulfonphthalein test in healthy sheep and in sheep with reductions in functional renal mass.

The phenolsulfonphthalein (PSP) plasma clearance and urinary excretion tests were applied to sheep before and after 50% and 75% reductions in functional renal mass. The PSP determinants found most useful as indicators of renal mass reduction were the 15-minute urinary excretion percentage and the 60-minute (PSP60) plasma concentration. Although both of these determinants could be used to detect renal mass reduction, the 15-minute PSP excretion percentage was the more sensitive. The PSP60 value was influenced by factors other than reduced nephron numbers; the contraction of the PSP volume of distribution that occurred after renal mass reduction was one important influencing factor. Overall, the PSP tests more accurately reflected the volume of blood delivered to the kidney than the proximal tubular secretory capacity.

An assessment of gastric ulcers in vivo: enhancement of urinary recovery after oral administration of phenolsulfonphthalein in rats.

The permeability of gastric wall barrier to phenolsulfonphthalein (phenol red), a poorly absorbed drug, was examined as an index of an assessment of gastric mucosal damages in vivo. The urinary recovery after oral administration of phenol red and the ulcer index of the stomach were significantly increased in rats subjected to restraint and water immersion stress. Gastric absorption of phenol red, examined by means of in situ loop technique, was increased significantly in stressed rats. However, the urinary recovery of the dye after intravenous administration did not change in ulcerated rats compared with the control. These findings suggest that the increase in the urinary recovery of phenol red is due to the increased gastric absorption. The healing period of 12 d was enough to restore to control levels both the ulcer index and the urinary recovery of the dye. Both indices remained nearly at control level by the pretreatment with atropine sulfate. Good correlation between extent of gastric damage and urinary excretion of phenol red was obtained within single groups of animals. This method may be utilized as a simple and noninvasive screening test for an assessment of gastric mucosal damages in vivo.

An assessment of indomethacin-induced gastrointestinal mucosal damage in-vivo: enhancement of urinary recovery after oral administration of phenolsulfonphthalein in rats.

The permeability of phenolsulfonphthalein(phenol red), a poorly absorbed drug, was examined as an index of an assessment of gastrointestinal mucosal damage in-vivo. The urinary recovery after oral administration of phenol red was significantly increased in rats with indomethacin-induced ulcers. However, the urinary recovery of phenol red after its intravenous administration was not affected by the ulcers. Gastric absorption of phenol red from the stomach was examined by means of the in-situ loop technique. A significant increase in disappearance of phenol red from the luminal solution was observed in rats orally pretreated with indomethacin. These findings suggest that the increase in urinary recovery of phenol red is due to increased gastrointestinal absorption. This method may be utilized as a simple, useful and non-invasive screening test for an assessment of gastrointestinal mucosal damage in-vivo.

Evaluation of uterine tube function in pony mares.

Two experimental procedures were investigated in order to assess their usefulness in diagnosing occlusion of the equine uterine tube. The starch grain test, which involves the injection of a starch suspension onto the ovary and the subsequent recovery of starch from the cervix, proved to be safe and reliable. Each tube could be investigated separately. It was found that when starch was injected onto the ovulating ovary on the day of ovulation, there was a delay of four to seven days before starch was recovered from the cervix. The phenolsulphonphthalein (PSP) test, which involves the deposition of dye solution into the uterus and its subsequent identification in urine after peritoneal absorption, was not reliable. Contamination of the urine occurred per vaginum, and the test was not unilaterally specific.

Use of the phenolsulphonphthalein dye test for fallopian tube patency in cattle.

Results of preliminary investigations of fallopian tube patency in cattle using a method based on intrauterine instillation of PSP dye, and detection of the dye in the urine, suggest that this test can provide a useful diagnostic aid in cases of bilateral occlusion. In such cases PSP dye is not evident in the urine two hours later. In normal animals dye is present within 30 minutes. In two animals with unilateral blockage dye appeared at an intermediate time between the normal and bilaterally occluded cases. Repetition of the test and the use of adequate volumes of dye to cause uterine distension may be necessary to eliminate false negatives.

Renal handling of phenol red. III. Bidirectional transport.

1. The renal excretion of phenol red and other phenolsulphophthalein dyes (bromophenol blue and bromothymol blue) was studied in clearance experiments on anaesthetized rabbits. 2. Net tubular excretion of phenol red reached a maximal value of 8 mumole/min at a plasma concentration of ultrafiltrable dye of about 0.1 mM and was decreased at higher plasma concentrations. Decreases in net tubular excretion at high plasma concentrations were also obtained for bromophenol blue and bromothymol blue suggesting tubular reabsorption in addition to tubular secretion of the dye. Conclusive evidence for reabsorption was provided by administration of probenecid which caused a fall in the excretion of the dyes below that filtered by the glomeruli. 3. Tubular reabsorption of phenol red during probenecid administration appeared to be proportional to the glomerular load and was increased under experimental conditions leading to a decrease of urinary pH. Experiments involving efflux of phenol red from liposomes gave no evidence of a significant role of transmembrane passage by non-ionic diffusion. It is suggested that the pH dependence of the reabsorptive process is the result of preferential reabsorption of the acid as compared to the basic form of the indicator dye across a hydrophilic pathway in the transporting membranes. 4. Clearance ratio of phenol red to that of p-aminohippurate at low plasma concentrations was about 0.3. They low degree of extraction of phenol red from renal plasma is attributed both to tubular reabsorption and binding of the dye by plasma proteins.

Validity of oral bioavailability estimates of phenolsulfonphthalein based on total urinary excretion from rats.

Urinary recovery of phenolsulfonphthalein from rats were determined after intracardial (0.075 mg) and oral (1.5 mg) doses. Although trace quantities of conjugated metabolites could be identified by TLC, the levels present did not introduce significant error into estimates of total phenolsulfonphthalein excretion if samples were assayed directly by colorimetric methods for only unchanged dye. The absolute availability of phenolsulfonphthalein based on urinary recovery under the present experimental conditions was estimated at 10.6%.