Absorption, Distribution and Excretion
Up to 15% of therapeutic doses of phenolphthalein are absorbed and excreted by the kidneys, mostly in bound form. If the urine is alkaline (pH 7 or higher), it will turn pink or red. Partially absorbed drug is also excreted via bile, and the resulting enterohepatic circulation may help prolong the laxative effect. In rats, bile excretion of phenolphthalein metabolites showed that pretreatment with hepatic microsomal enzyme inducers increased bile excretion, while administration of enzyme inhibitors reduced bile excretion after administration of the parent compound, but this effect was not observed after administration of the metabolites. Following intravenous injection, phenolphthalein glucuronide (I) was excreted faster than phenolphthalein (II), suggesting that the rate of absorption of (I) from the blood is limited, exceeding the effect of the lack of prior binding reaction. For more complete data on the absorption, distribution, and excretion of phenolphthalein (14 in total), please visit the HSDB records page.

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Metabolism/Metabolites
In 22 lactating women, following a single dose of 200–800 mg, conjugated phenolphthalein (not unmetabolized phenolphthalein) was secreted into breast milk at concentrations up to 1.0 μg/mL. Sixteen women experienced defecation after administration, but none of the lactating infants experienced diarrhea.
Phenolphthalein-β-D-glucuronide was generated in rats and mice. /Excerpt from table/
In rodents and dogs, phenolphthalein is absorbed in the intestine and undergoes extensive first-pass metabolism via uridine diphosphate glucuronyl transferase (UDPGT) in the intestinal epithelium and liver, almost completely converting to its glucuronide. In guinea pigs, trace amounts of sulfate-conjugated metabolites have been detected in isolated mucosal fragments derived from the jejunum and colon. The primary route of phenolphthalein excretion in rats is fecal excretion, while in mice, both urinary and fecal excretion are important. Metabolites identified in urine and feces included phenolphthalein glucuronide, phenolphthalein sulfate, and phenolphthalein hydroxide. The major metabolite was phenolphthalein glucuronide. Three minor metabolites were detected. A sulfate conjugate and a hydroxylated metabolite were identified by comparison of retention times with synthetic standards using ¹H NMR and/or mass spectra. A diglucuronide conjugate was preliminarily identified. Extensive bile excretion in rats (35% of the dose excreted within 6 hours); the only product detected in bile was phenolphthalein glucuronide. The classic compartment pharmacokinetic model was used to describe the systemic plasma concentration-time curve after a single intravenous bolus injection of phenolphthalein; it was used to simulate the changes in plasma concentration over 24 hours. The results showed that the long half-life was an artifact caused by circulation.

Interactions
Pretreatment of rats with methotrexate sodium (1 mg, orally, once daily for 5 days) or vincristine sulfate (0.03 mg/kg, intravenously, once weekly for 3 weeks) significantly reduced bile excretion of phenolphthalein (10 mg/kg, intravenously), indicating decreased liver function.

[1]. Color indicator for supramolecular polymer chemistry: phenolphthalein-containing thermo- and pH-sensitive N-(Isopropyl)acrylamide copolymers and β-cyclodextrin complexation. Macromol Rapid Commun. 2013 Jul 12;34(13):1085-9.

According to the U.S. Food and Drug Administration (FDA) and the National Toxicology Program (NTP), phenolphthalein may be carcinogenic. Phenolphthalein is a white or pale yellow to pale orange fine crystalline powder, odorless. Its aqueous solution is acidic. It is colorless below pH 8.5 and pink to deep red above pH 9. It is colorless under strongly alkaline conditions. It is tasteless. (NTP, 1992) Phenolphthalein belongs to the phenolic class of compounds, and its structure is similar to 2-benzofuran-1(3H)-one. Due to concerns about its carcinogenicity, phenolphthalein was withdrawn from the market in Canada in 1997. Phenolphthalein has been reported to be found in Caragana conferta, and relevant data are available. Phenolphthalein is an organic compound used as a laboratory reagent and pH indicator. Phenolphthalein acts as a laxative by stimulating the intestinal mucosa and contracting smooth muscle. However, due to suspected carcinogenicity, phenolphthalein is no longer used as a laxative. In 1997, Canada withdrew phenolphthalein due to carcinogenicity concerns. A colorless acid-base indicator, it turns pink to red in acidic solutions but becomes alkaline. It is used medically as a laxative. Its use as a laxative has a history of over a century. Its mechanism of action involves altering the absorption of body fluids and electrolytes, leading to net fluid accumulation in the intestines and causing diarrhea. Increased concentrations of cyclic adenosine monophosphate (cAMP) in clonal mucosal cells may alter the permeability of these cells, leading to net fluid accumulation and a laxative effect. Phenolphthalein can also directly or reflexively enhance the activity of the small intestine. It primarily acts on the colon, taking effect approximately 6 hours after ingestion. After oral administration, phenolphthalein is thought to dissolve in intestinal fluid and bile and stimulate intestinal muscles, particularly the colonic muscles. Phenolphthalein increases the amount of intestinal fluid in the rat colon, apparently by stimulating the biosynthesis of prostaglandin E in the colon. Following administration of phenolphthalein, intestinal water absorption was measured in six ileostomy patients and rats. The results indicated that part of the laxative effect stemmed from inhibition of water absorption in the large and small intestines. Hydroxyphenolphthalein (PT-CAT), a catechol metabolite of PT, was recently identified as a potential molecule contributing to PT toxicity/carcinogenicity. We hypothesized that PT-CAT inhibits catechol-O-methyltransferase (COMT), thereby enhancing the genotoxicity of PT-CAT itself or endogenous catechol estrogens (CEs) in susceptible tissues. This study aimed to determine, in vitro and in vivo, the effects of PT treatment and PT-CAT itself on COMT-mediated 4- and 2-hydroxyestradiol metabolism. Female mice were sacrificed after 21 days of PT treatment (50 mg/kg/d). Urinary PT-CAT concentrations plateaued after 7 days of exposure. O-methylated metabolites of PT-CAT were detected in feces. In vitro studies showed that PT treatment led to an increase in free catechol esters (CE), which are normally cleared by catechol-O-methyltransferase (COMT), while COMT's ability to clear hepatic catechol esters decreased. In vitro studies showed that PT-CAT is a substrate of COMT, and its kinetic properties are consistent with those of endogenous substrates. PT-CAT is a potent mixed inhibitor of catechol estrogen O-methylation, with an IC50 value of 90-300 nM.

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Therapeutic Uses
Laxative; Indicator and Reagent
…has been widely used as a laxative. …It exists in a variety of proprietary formulations.
Because…it usually takes at least 6 hours to produce a laxative effect after oral administration, it is usually taken at bedtime to allow it to take effect the following morning. Due to the presence of adverse reactions, the use of these drugs should be limited to 10 consecutive days. /Diphenylmethane Derivatives/
(Veterinary Drugs): Formerly used as a laxative.
Laxatives; Acid-base indicators.

Drug Warnings

Phenolphthalein use by breastfeeding women may cause diarrhea in infants.
Patients should be informed that urine and stool color may change.

C20H14O4

318.32

318.089

77-09-8

4764

White to off-white solid powder

1.4±0.1 g/cm3

557.8±50.0 °C at 760 mmHg

258-263 °C

206.5±23.6 °C

0.0±1.6 mmHg at 25°C

1.693

2.63

2

4

2

24

438

0

KJFMBFZCATUALV-UHFFFAOYSA-N

InChI=1S/C20H14O4/c21-15-9-5-13(6-10-15)20(14-7-11-16(22)12-8-14)18-4-2-1-3-17(18)19(23)24-20/h1-12,21-22H

3,3-bis(4-hydroxyphenyl)-2-benzofuran-1-one

Phthalimetten; Euchessina; Phenolphthalein

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~157.07 mM)

Solubility in Formulation 1: 2.5 mg/mL (7.85 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (7.85 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 2.5 mg/mL (7.85 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)