Toxicokinetics of phenolphthalein in male and female rats and mice

• Published in: Toxicological sciences 2000-08, Vol.56 (2), p.271-281
• Main Authors: COLLINS, B. J, GRIZZLE, T. B, DUNNICK, J. K
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Cathartics - pharmacokinetics; Chemical agents; Drug toxicity and drugs side effects treatment; Female; Male; Medical sciences; Mice; Mice, Inbred C57BL; Miscellaneous (drug allergy, mutagens, teratogens...); Pharmacology. Drug treatments; phenolphthalein; Phenolphthalein - administration & dosage; Phenolphthalein - pharmacokinetics; Phenolphthalein - toxicity; phenolphthalein glucuronide; Rats; Rats, Inbred F344; Sex Factors; Species Specificity; Tumors
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/56.2.271

Phenolphthalein (PTH), which has been used as the active ingredient in a number of prescription and over-the-counter laxative products, is a rodent chemical carcinogen in multiple organs in the NTP 2-year bioassay at doses of 291-2927 mg/kg. This paper describes the toxicokinetics and estimates the internal dose of PTH administered as a single iv or gavage dose, or ad libitum for 14 days in feed to F344 rats, B6C3F1 mice, p53 (+/-) mice, and C57BL mice at doses that bracketed those used in the bioassay. Plasma concentrations for free phenolphthalein (PTH-F) and phenolphthalein glucuronide (PTH-G) were obtained for each dose regimen. Total phenolphthalein (PTH-T) was calculated as the sum of the molar concentrations of PTH-F and PTH-G. Noncompartmental pharmacokinetic models were used to calculate the area under the curve (AUC) from 0 h to infinity (AUC(infinity)), clearance (Cl), and oral bioavailability (F) for PTH-F; and were used to calculate AUC(infinity), t((1/2)), and relative absorption (Q) for PTH-T. After iv administration, PTH-F rapidly declined in rats and mice; PTH-T rose rapidly to Cmax and slowly declined 6-8 h after dosing, with no sex-related differences for rats or mice. For feed studies, mean plasma concentration (f1.gif" BORDER="0">(infinity)) and 24-h area under the curve (AUC(24h)) values were calculated. Results from feed studies showed no dose response in rat plasma PTH-F above approximately 50 mg/kg. Rat PTH-T AUC(24h) and f1.gif" BORDER="0">(infinity) were linear with doses up to approximately 650 mg/kg. In B6C3F1 mice, PTH-F and PTH-T AUC(24h) increased nonlinearly with doses above approximately 165 mg/kg. PTH is well absorbed and readily converted to PTH-G when administered in feed to rats and mice, except at the highest bioassay doses, where PTH absorption may be saturated.