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.

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.

Enhanced rectal absorption of cefmetazole and cefoxitin in the presence of epinephrine metabolites in rats and a high-performance liquid chromatographic assay for cephamycin antibiotics.

4-Hydroxy-3-methoxymandelic acid and 3,4-dihydroxymandelic acid were found to be potent adjuvants for the rectal absorption of water-soluble compounds in rats. Both adjuvants enhanced the absorption of two cephamycin antibiotics, cefmetazole and cefoxitin. Maximum plasma levels of the antibiotics were obtained within 30 min after rectal administration. The bioavailability of both antibiotics appeared to depend on the concentration of the adjuvant in the microenema, the dosage form used in these experiments. Instead of a microbial assay, a new chemical method involving high-performance liquid chromatography with an ion-pairing technique was developed for analyzing the cephamycin antibiotic plasma levels.

[Clinico-biochemical study of experimental renal injuries in rats. 3. Relations between serum half-life of phenolsulfonphthalein and renal injuries].

The serum half-life of PSP(PSP t/2) was determined in normal and nephropathy rats by repeated blood collection under an unanesthetized condition to estimate its usefulness as a renal functional parameter. In normal rats, the serum disappearance curve of PSP (5 mg/kg) could be resolved into two exponential components, and the mean PSP t/2 in the second component was 12 min (n=100). About 71% of the PSP loaded was excreted in urine and 19% in bile. A single subcutaneous injection of HgCl2 delayed the serum disappearance of PSP and simultaneously decreased its urinary excretion and increased its biliary excretion. The serum protein binding ratio of PSP became higher when the serum concentration of PSP was decreased, while it became lower when the serum albumin level was decreased. PSP t/2 in rats treated with gentamicin or puromycin amino-nucleoside as well as that in rats given HgCl2 was increased in correlation with changes in common renal functional parameters such as serum urea nitrogen, serum creatinine, urinary protein and morphologic changes of the kidney. Masugi-type nephritis rats showed no change in PSP t/2. Moreover, PSP t/2 was well correlated with the maximal tubular secretion rate of p-amino-hippuric acid. Since PSP t/2 can be determined periodically on the same animal, it is considered to have effective application as a renal functional test in rats, especially for examining tubular secretion.

Relationship of selected clinical renal function tests to glomerular filtration rate and renal blood flow in cats.

Results of 3 clinical tests of renal function--urine concentrating ability and disappearance of plasma phenosulfonphthalein (PSP) and sodium sulfanilate (SS) were compared with those of 2 classic tests, glomerular filtration rate (GFR) and renal blood flow (RBF), in 11 cats before and after reduction of renal mass. Values (mean +/- SD) obtained from normal cats were maximum urine concentration of 2,270 +/- 407 mOsm/kg (specific gravity values of 1.067 +/- 0.015); T 1/2 for plasma disappearance of PSP of 24.27 +/- 3.5 minutes; T 1/2 for plasma disappearance of SS of 44.42 +/- 5.67 minutes; GFR of 2.94 +/- 0.32 ml/min/kg; and RBF of 10.61 +/- 1.71 ml/min/kg. After reduction of renal mass by vascular ligation and nephrectomy, the cats became azotemic and had significant decreases in GFR and RBF (P less than 0.005), but still were able to concentrate urine to a considerable extent. Both maximum urine concentration and PSP plasma decay were poorly correlated with GFR (r = 0.4060 and 0.3694, respectively) and RBF (r = -0.3439 and -0.3427). Sulfanilate half-life had better correlation with GFR (r = -0.7004) than with RBF (r = -0.5716). Both GFR and RBF increased significantly (P less than 0.005) between postsurgical weeks 1 and 9. It was concluded that experimental cats with azotemia retain considerable ability to concentrate urine and that the SS test is superior to both the PSP test and urine concentration test for clinical estimation of renal function.

Simultaneous assay of bromosulfophthalein and phenolsulfonphthalein in the blood as a test of hepatic and renal functional capacity.

A spectrophotometric procedure for the assay of bromosulfophthalein and phenolsulfonphthalein in the plasma of various animal species and the half-life of the two dyes in plasma representing respectively the rate of liver depuration and that of kidney depuration are described. The method is easy to execute and lends itself particularly well for the simultaneous assessment of hepatic and renal function in the same animal.

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.

Clinical study on correlation with the 60-min plasma phenolsulfonphthalein concentration and other renal function tests.

An analysis of the reliability of the 60-min plasma phenosulfonphthalein concentration (PSP60) as a renal function test has been made in 40 patients with or without urinary dead space. PSP60 correlates with 15-min urinary PSP excretion and 24-hour endogenous creatinine clearance in patients without urinary dead space. 15-min urinary PSP excretion showed unreliability as a renal function test in patients with urinary dead space. However, we confirmed that PSP60 and 24-hour endogenous creatinine clearance were reliable indicators of renal function in these patients.

Excretion of phenol red and its glucuronide in the dogfish shark.

1. The biliary and urinary excretion of phenol red and its glucuronide was measured in dogfish sharks, Squalus acanthias, in both intact animals and animals with biliary fistula. 2. Phenol red is extensively metabolized to its glucuronide by the dogfish shark and both forms of the compound are actively transported into bile and urine. 3. Both compounds are transferred from plasma to urine and bile against a large concentration gradient; the transfer process is saturable most easily in the renal compartment but also in the hepatic compartment; and both excretion routes for the free drug and the glucuronide are inhibited by probenecid. 4. There were no significant differences in the 48 h biliary excretion of total (free + glucuronide) phenol red, but the urine or intact fish contained two-fold more total drug than did animals with fistulae.

[Investigations of changes in the phenolsulphonphthalein plasma levels in pregnant women with EPH syndrome (author's transl)]. / Untersuchungen über Veränderungen des Phenolsulfonphthalein-Plasmaspiegels bei Graviden mit EPH-Syndrom

In 53 patients, 24 healthy pregnant women and 29 patients with EPH (edema, proteinuria, hypertension) syndrome, the intravenous phenolsulphonphthalein test was performed between the 32nd and 42 weeks of pregnancy. At the same time, the serum creatinine and estrogen excretion in the 24 hour urine were determined. According to this, normal pregnancy and also pregnancies with one or more symptoms of the EPH syndrome without raised blood pressure do not cause changes of the PSP plasma level. A statistically significant rise in the PSP plasma level is only found with a blood pressure of 140/90 mm Hg, and simultaneously a close correlation to the estrogen excretion in the urine (r = -0.4) and the blood pressure (r = 0.6). Estrogen excretion is reduced with increasing blood pressure (r = -0.75). No correlation could be established between the PSP serum level and the creatinine in the serum.