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Toxicological Sciences 56, 271-281 (2000)
Copyright © 2000 by the Society of Toxicology

Toxicokinetics of Phenolphthalein in Male and Female Rats and Mice

B. J. Collins*,1, T. B. Grizzle{dagger} and J. K. Dunnick*

* National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709-2233; and {dagger} Triangle Pharmaceuticals, Inc., Durham, North Carolina 27707

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{infty}), clearance (Cl), and oral bioavailability (F) for PTH-F; and were used to calculate AUC{infty}, t1/2, 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 ({infty}) and 24-h area under the curve (AUC24h) values were calculated. Results from feed studies showed no dose response in rat plasma PTH-F above ~50 mg/kg. Rat PTH-T AUC24h and {infty} were linear with doses up to ~650 mg/kg. In B6C3F1 mice, PTH-F and PTH-T AUC24h increased nonlinearly with doses above ~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.

Key Words: phenolphthalein; toxicokinetics; phenolphthalein-glucuronide; AUC; iv; gavage; feed; multiple routes; rat; mouse.


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