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  5. Comparative pharmacokinetics of Zileuton’s active pharmaceutical ingredient, nanocrystal-drug, and physical mixture in male and female Sprague Dawley rats
  1. The FDA Science Forum

2023 FDA Science Forum

Comparative pharmacokinetics of Zileuton’s active pharmaceutical ingredient, nanocrystal-drug, and physical mixture in male and female Sprague Dawley rats

Download the Poster (PDF; 1.59 MB)
Authors:
Poster Author(s)
Muthumula, Chandra Mohan Reddy, FDA/NCTR; Wickramaratne, Bhagya, FDA/NCTR; Khare, Sangeeta, FDA/NCTR; Chakder, Sushanta, FDA/CDER; Kuppan, Gokulan, FDA/NCTR
Center:
Contributing Office
National Center for Toxicological Research

Abstract

Poster Abstract

The biopharmaceutical classification system (BCS) has been used as a prognostic tool to determine the bioavailability of an oral drug based on its solubility and permeability properties. Zileuton, a 5-lipoxygenase inhibitor used to treat chronic asthma, is classified as BCS class II drug due to its poor solubility and high permeability. To address solubility issues and improve bioavailability of a BCS class II drug, Zileuton was used as a model drug to develop a nanocrystal-drug formulation. In this study we evaluated the sex dependent changes in the pharmacokinetic properties of Zileuton in 10 weeks old male and female Sprague Dawley rats following oral administration of active pharmaceutical ingredient (API; 30 mg/kg bw), nanocrystal-drug formulation (ND; 30 mg contains 7.5 mg of API) and physical mixture (PM; 30 mg contains 7.5 mg of API) using gelatin capsules. A reproducible HPLC technique was developed to determine the concentration of Zileuton in the ileum (15 days post treatment), plasma (1, 2, 4, 6, and 24h post treatment), and urine (24h post treatment) samples. The results of this study showed that female rats had lower Zileuton concentrations in the ileum after oral administration of the API and nanodrug formulation than male rats. Following treatment with API, ND, and PM, plasma Zileuton concentrations were found to be higher in female rats than in male rats. The lower plasma Zileuton concentration in the male rats can be correlated to the higher expression of phase-1 and phase-II metabolic enzymes in the intestinal tissue. The Tmax of Zileuton in the male rats was found to be 2h after ND and PM treatment, compared to 1h after API treatment. In the female rats, the Tmax of Zileuton was 1h following administration of ND and PM, and 2h following administration of API. Following administration of ND and PM, male rats had a higher concentration of Zileuton in their urine at 24h than female rats. Overall, pharmacokinetic variations of Zileuton were observed between male and female rats following oral administration of API, ND, and PM. This study justifies further investigation of the ND in the translational model of asthma.

Poster Image
Comparative pharmacokinetics of Zileuton’s active pharmaceutical ingredient, nanocrystal-drug, and physical mixture in male and female Sprague Dawley rats

Download the Poster (PDF; 1.59 MB)

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