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PubMedDate not supplied

A pharmacokinetic model for enterohepatic recirculation in the rat: phenolphthalein, a model drug.

A classical compartmental pharmacokinetic model was developed to describe the systemic blood concentration-time profile of phenolphthalein and its glucuronide conjugate (total 3H) following a single intravenous bolus injection of [3H]phenolphthalein. The model incorporates a biliary transport system, including a finite lag time for the biliary phenophthalein glucuronide to be hydrolyzed in the intestine before absorption. Data obtained from bile duct-cannulated animals were fit to the same model excluding any component for intestinal absorption. Agreement between the rate constants obtained for both fits indicates that the model is internally consistent. The model was then used to simulate a 24-hour time-course of phenolphthalein-equivalent blood concentrations which indicates that the long apparent half-lives calculated during this period are artifacts of recirculation.

Animals↗
PubMed1998

Metabolism and disposition of phenolphthalein in male and female F344 rats and B6C3F1 mice.

A recent 2-year carcinogenicity/toxicology study determined that phenolphthalein (PHTH) is a multisite carcinogen in both mice and rats at all doses evaluated. In response to this finding the metabolism and disposition of PHTH has been evaluated in both F344 rats and B6C3F1 mice at a single oral dose of 800 mg/kg. This dose fell within the range previously found to be carcinogenic in rats and mice. Studies were also performed using 1 and 50 mg/kg doses. At 800 mg/kg recovery of [14C]PHTH after 72 h was near 100% in females but closer to 75% in males. Radioactivity was primarily recovered in the feces in rats (> 90%), while mice excreted 30-40% of administered activity in the urine. There was no significant retention of radioactivity in tissues by 72 h and no significant accumulation of radioactivity in any tissue at any time point. Covalent binding to protein in target tissues, bone marrow and ovary, was at or less than the pmol/mg protein range. The major metabolite was PHTH glucuronide. Three minor metabolites were detected. A sulfate conjugate and and a hydroxylated metabolite were identified by comparison of retention times and 1H NMR and/or mass spectra with synthetic standards. A diglucuronide conjugate was tentatively identified. Biliary elimination was extensive in rats (35% of dose within 6 h); the only product detected in bile was phenolphthalein glucuronide.

Administration, Oral↗
PubMed1984

The production of arachidonate lipoxygenase products by rat intestine is increased by phenolphthalein.

Rat isolated intestine incubated in Krebs solution converted exogenous [14C]arachidonic acid into products that chromatographed with prostaglandins, leukotriene B4 and 5-hydroxy-eicosatetraenoic acid. The accumulation of these products was increased by phenolphthalein 3.14-1570 microM and reduced by indomethacin 2.8 microM. This raises the possibility that laxation by phenolphthalein involves the formation of arachidonate lipoxygenase and cyclo-oxygenase products.

Animals↗
PubMed1993

Effect of psyllium, calcium polycarbophil, and wheat bran on secretory diarrhea induced by phenolphthalein.

BACKGROUND: Fiber and water-holding agents are used for the treatment of constipation. In what may appear to be a paradox, they are sometimes also used for the treatment of diarrhea; it has been proposed that they sequester water from liquid stools and/or increase the ratio of fecal solids to fecal water and thereby improve stool consistency. The purpose of the present study was to test the validity of this hypothesis in normal subjects in whom secretory diarrhea was induced by phenolphthalein. METHODS: In random sequence, 9 subjects with phenolphthalein-induced diarrhea were treated with placebo, psyllium, calcium polycarbophil, or wheat bran. RESULTS: Calcium polycarbophil and wheat bran had no effect on fecal consistency or on fecal viscosity. By contrast, psyllium made stools firmer and increased fecal viscosity. In a dose-response study in 6 subjects, doses of 9, 18, and 30 g of psyllium per day caused a near linear increase in fecal viscosity. CONCLUSION: Psyllium, but not calcium polycarbophil or wheat bran, improves fecal consistency and viscosity in subjects with experimentally-induced secretory diarrhea.

Acrylic Resins↗
PubMed1984

Glucuronidation in the reindeer: dietary modification in the UDP-glucuronosyltransferase activity with 4-nitrophenol, 1-naphthol and phenolphthalein as acceptors.

The UDP-glucuronosyltransferase activity towards 4-nitrophenol, 1-naphthol and phenolphthalein was measured from the hepatic microsomes of the reindeer (Rangifer tarandus tarandus) after summer, autumn and winter feeding periods. The microsomes were digested with trypsin or digitonin. The UDP-glucuronosyltransferase activity with 4-nitrophenol and 1-naphthol as aglycones was lower in reindeer on winter food than in ones on summer food after trypsin and digitonin digestion. The activity towards phenolphthalein was the same in each feeding period. The different seasonal feeding affects the structure of microsomal membranes and this is reflected as modifications of the UDP-glucuronosyltransferase towards different substrates.

Animals↗
PubMed1995

Comparison of reversed-phase liquid chromatography with colorimetry for analysis of phenolphthalein preparations.

The high-performance liquid chromatography (HPLC) method of the United States Pharmacopeia has been compared with the colorimetric method of the British Pharmacopoeia for the assay of phenolphthalein in various preparations. Results are presented for the linearity, sensitivity and reproducibility of the two methods. The HPLC method was considered to be more convenient for routine analysis of the preparations of phenolphthalein.

Calibration↗
PubMed1994

Nitric oxide as a mediator of bisacodyl and phenolphthalein laxative action: induction of nitric oxide synthase.

Bisacodyl and phenolphthalein are diphenylmethane laxatives that have effects on intestinal water and electrolyte transport and smooth muscle contractility. Nitric oxide (NO) is produced in the intestine, where it stimulates electrolyte secretion and relaxes smooth muscle. Therefore, we studied in rats the effect of these laxatives on diarrhea, fluid transport in vivo, gastrointestinal transit and NO synthase activity in the absence and presence of inhibitors of NO synthesis. Both laxatives (50 mg/kg p.o.) produced diarrhea, which was delayed in onset by 25 mg/kg (i.p.) of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The L-NAME effect was reversed by the NO donor isosorbide-5-mononitrate (30-120 mg/kg i.p.). L-Arginine (600 and 1500 mg/kg i.p.) prevented the inhibitory effect of L-NAME on diarrhea. The laxatives evoked water and electrolyte secretion and enhanced the transit of a suspension of charcoal through the gastrointestinal tract. This was inhibited by L-NAME but not D-NAME. The inhibitor of inducible NO synthase, dexamethasone (0.03-0.3 mg/kg i.p.), prevented the effects of both laxatives on electrolyte and water transport. Stimulation by these drugs of NO synthase was also inhibited by dexamethasone. The results demonstrate that bisacodyl and phenolphthalein stimulate water and electrolyte secretion, promote transit of intraluminal contents and produce diarrhea in association with enhanced production of NO. Furthermore, it appears that the NO is derived principally from activation of an inducible form of NO synthase.

Amino Acid Oxidoreductases↗
PubMed1975

The radiometric assay of alkaline phosphatase activity with 125-I-labelled phenolphthalein monophosphate.

The coupling of 125-I to phenolphthalein monophosphate is described. Hydrolytic cleavage of the phosphate group by alkaline phosphatases (EC 3.1.-3.1) releases labelled phenolphthalein which is extracted into ethyl acetate at pH 10. This forms the basis of a sensitive assay for the enzyme with the advantages of sensitivity and rapidity from the use of a gamma-emitter. Results with Escherichia coli and calf intestine alkaline phosphatases are presented.

Alkaline Phosphatase↗
PubMed1975

The radiometric assay of microsomal UDP-glucuronyltransferase using 125I-labelled phenolphthalein.

A rapid and sensitive method is described for assaying UDP-glucuronyl-transferase (EC 2.4.1.17) activity. The substrate is the relatively apolar phenolphthalein, labelled with 125I on one of its two phenolic rings leaving a free hydroxyl group for glucuronidation. Extraction with ethyl acetate leaves the glucuronide in the aqueous reaction medium which is then counted. Less than 10 mug microsomal protein is required and the glucuronidation of 10 ng 125I-labelled phenolphthalein (0.03 nmoles) is easily detected.

Animals↗
PubMed1991

NMR-monitored solid-phase extraction of phenolphthalein glucuronide on phenylboronic acid and C18 bonded phases.

Preliminary studies have been undertaken to evaluate the potential of immobilized phenylboronic acid (PBA) for the solid-phase extraction (SPE) of glucuronide metabolites from urine. These studies have demonstrated that immobilized PBA can be used to specifically extract phenolphthalein glucuronide (5 mM) from urine. Urine samples were loaded onto the PBA SPE column in glycine buffer (pH 8.5) and were eluted using methanol-1% HCl (90:10, v/v). The overall recoveries of the phenolphthalein glucuronide for this procedure were high (99%), which compared well with similar studies carried out concomitantly on C18 bonded columns (93%).

Boronic Acids↗
PubMedDate not supplied

Acute phenolphthalein ingestion in children. A retrospective review.

The Patient Management Exchange for this edition of the Journal features a research study on phenolphthalein ingestion done at the Pittsburgh Poison Center. The purpose of selecting this article was twofold. First, the material presented about the management of phenolphthalein ingestion in children is valuable information for health care practitioners working in ambulatory settings. Second, this work is an excellent illustration of how research can be incorporated into one's clinical practice. This study also demonstrates that research does not always involve a long and cumbersome process. Instead, research can evolve from the need of health care professionals to answer a simple question that is raised about a particular aspect of their patient practice.

Charcoal↗
PubMed1977

Biliary excretion of some anionic derivatives of diethylstilboestrol and phenolphthalein in the guinea pig.

The metabolic fates and modes of excretion of diethylstilboestrol mono[35S]sulphate and diethylstilboestrol di[35S]sulphate were studied in the guinea pig. Comparative studies were also made with [G-3H]diethylstilboestrol and phenolphthalein di[35S]sulphate. Diethylstiboesterol di[35S]sulphate was extensively eliminated in the bile unchanged. After administration of diethylstilboestrol mono[35S]sulphate, extensive biliary elimination of radioactivity was also recorded. Radioactive components were identified as diethylstilboestrol disulphate, diethylstilboestrol monosulphate monoglucuronide and unchanged diethylstilboestrol monosulphate. When [G-3H]diethylstilboestrol was administered, 3H-labelled diethylstilboestrol monoglucuronide, diethylstilboestrol monosulphate monoglucuronide and diethylstilboestrol disulphate appeared in the bile. Phenolphthalein di[35S]sulphate was excreted unchanged in bile. These findings are discussed in relation to studies carried out in the rat [Barford, Olavesen, Curtis & Powell (1977) Biochem. J. 164, 423--430] and species differences are related to differences in enzyme activities in rat and guinea-pig liver.

Animals↗
PubMed2001

Chromosome 11 loss from thymic lymphomas induced in heterozygous Trp53 mice by phenolphthalein.

C57BL/6 p53 (+/-) N5 mice heterozygous for a null p53 allele were given phenolphthalein to learn more about mechanisms of carcinogenesis and to evaluate the p53-deficient mouse as a tool for identifying potential human carcinogens. DNA samples isolated from 10 phenolphthalein-induced thymic lymphomas were analyzed for loss of heterozygosity (LOH) at the Trp53 locus and simple sequence length polymorphic (SSLP) loci. The initial screening revealed remarkable results from only chromosome 11. Allelotyping at approximately five centiMorgan intervals, we found SSLP heterozygosity for C57BL/6 and 129Sv over much of chromosome 11. In the tumors, treatment-related LOH was apparent on chromosome 11 at each of the 28 informative loci examined. The strain-specific polymorphism lost from individual tumors allowed us to deduce the distribution of alleles along the length of the maternal and paternal chromosomes 11. The allelic patterns indicate that mitotic homologous recombination occurred during embryogenesis if breeding protocols were carried out as described. The mitotic recombination observed may be attributable to p53 haploinsufficiency for normal suppression of mitotic recombination.

Animals↗
PubMed1968

The effect of temperature on the competitive inhibition of glucose transfer in human erythrocytes by phenolphthalein, phloretin and stilboestrol.

1. Phenolphthalein, like other diphenols, has been shown to be a competitive inhibitor of the facilitated transfer system for glucose in the human erythrocyte.2. The concentration producing 50% inhibition is lower at low temperatures and increases steadily over the temperature range 10-40 degrees C. An Arrhenius plot of the results gives a slope of 19,300 cal/mole.3. The effect of temperature on inhibition by phloretin and stilboestrol has also been studied. The temperature variation of the concentration of phloretin giving 50% inhibition is similar to that for phenolphthalein, but that for stilboestrol is much less.4. There is a high cell/medium distribution ratio for stilboestrol, and the possibility that this may affect the temperature dependence of the aqueous concentrations required to give 50% inhibition is discussed.

Animals↗
PubMedDate not supplied

Determination of phenolphthalein and methylene blue by first derivative spectrophotometry and potassium nitrate by direct spectrophotometry in a pharmaceutical formulation.

A rapid first derivative visible spectrophotometric determination is described for the simultaneous determination of phenolphthalein (PHP) and methylene blue (MB) in the presence of potassium nitrate (KNO3). Potassium nitrate is also determined by direct visible spectrophotometric method in the presence of phenolphthalein and methylene blue without any interference. The methods have been applied to the determination of the three compounds in a commercial dosage form. The calibration graphs were linear in the range of 0.30-3.20 mg mL-1 for MB and 0.80-3.18 micrograms mL-1 for PHP and 0.80-8.10 micrograms mL1 for KNO3. The specificity, accuracy and precision of the methods have been assessed.

Calibration↗
PubMed1967

Biliary excretion of foreign compounds. Biphenyl, stilboestrol and phenolphthalein in the rat: molecular weight, polarity and metabolism as factors in biliary excretion.

1. The extent of biliary excretion of biphenyl, tetralin, stilboestrol and phenolphthalein was studied in the rat. 2. Biphenyl and its 4-hydroxy and 4,4'-dihydroxy derivatives are extensively excreted in the bile as glucuronides in amounts increasing in order of molecular weight. 3. Stilboestrol and its glucuronide are excreted almost quantitatively in the bile mainly as the monoglucuronide, as are also phenolphthalein and its glucuronide. 4. Tetralin is excreted to the extent of about 13% of the dose, mainly as ac-tetralyl glucuronides. 5. The results and those of Abou-El-Makarem, Millburn, Smith & Williams (1967) are discussed and it is concluded that the extent of biliary excretion of foreign compounds in rats depends on their molecular weight and their possessing a strongly polar anionic group. There appears to be a minimum value of this molecular weight below which little biliary excretion (i.e. not more than 5-10% of the dose) occurs. There is some latitude in the choice of this molecular weight, which is about 325+/-50. The necessary molecular weight and polar group can be acquired by metabolism. Above this minimum value biliary excretion increases with molecular weight. It is suggested that the mechanism of the biliary excretion of foreign compounds may be similar to that of conjugated bile acids, which are highly polar and whose molecular weights exceed 400.

Journal Article↗
PubMed2000

Phenolphthalein metabolite inhibits catechol-O-methyltransferase-mediated metabolism of catechol estrogens: a possible mechanism for carcinogenicity.

Phenolphthalein (PT), used in over-the-counter laxatives, has recently been identified as a multisite carcinogen in rodents, but the molecular species responsible for the carcinogenicity is not known. A catechol metabolite of PT, hydroxyphenolphthalein (PT-CAT), was recently identified and may be the molecular species responsible for at least part of the toxicity/carcinogenicity of PT. We hypothesize that PT-CAT inhibits the enzyme catechol-O-methyltransferase (COMT) and therefore potentiates genotoxicity by either PT-CAT itself or the endogenous catechol estrogens (CEs) in susceptible tissues. The present studies were conducted to determine the effects of PT treatment and PT-CAT itself on the COMT-mediated metabolism of 4- and 2-hydroxyestradiol both in vitro and in vivo. Female mice were treated with PT (50 mg/kg/d) for 21 days and then euthanized. PT-CAT concentration in urine reached plateau levels by 7 days of exposure. An O-methylated metabolite of PT-CAT was detected in feces. In vitro experiments demonstrated that PT treatment resulted in an increase in free CEs, which are normally cleared by COMT and a concurrent decrease in the capacity of hepatic catechol clearance by COMT. In vitro, PT-CAT was a substrate of COMT, with kinetic properties within the range measured with endogenous substrates. PT-CAT was an extremely potent mixed-type inhibitor of the O-methylation of the catechol estrogens, with 90-300 nM IC50s. The above data, when taken together, suggest that chronic administration of PT may enhance metabolic redox cycling of both PT-CAT and the catechol estrogens and this, in turn, may contribute to PT-induced tumorigenesis.

Animals↗