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Evaluation of gender differences in the pharmacokinetics of oral zileuton nanocrystalline formulation using a rat model.
Muthumula, Chandra Mohan Reddy; Khare, Sangeeta; Jog, Rajan; Wickramaratne, Bhagya; Lee, Angela; Chakder, Sushanta; Burgess, Diane J; Gokulan, Kuppan.
Afiliación
  • Muthumula CMR; Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, United States of America.
  • Khare S; Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, United States of America.
  • Jog R; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States of America.
  • Wickramaratne B; Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, United States of America.
  • Lee A; Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, United States of America.
  • Chakder S; Center for Drug Evaluation and Research, US Food and Drug Administration, White Oak Campus, Silver Spring, MD 20993, United States of America.
  • Burgess DJ; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States of America.
  • Gokulan K; Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, United States of America.
Int J Pharm X ; 7: 100254, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38774112
ABSTRACT
Zileuton is a leukotriene inhibitor used to treat asthma. As a BCS class II drug it exhibits challenges with solubility which likely impact its absorption. As patient gender significantly impacts the pharmacokinetics of many drugs, this study aimed to investigate potential gender-based pharmacokinetic differences after oral zileuton administration in rats. Male and female Sprague Dawley rats received single oral gavage doses of pure zileuton as an active pharmaceutical ingredient (30 mg/kg body weight (bw)), physical mixture (PM; at 30 mg/kg bw of the formulation contains zileuton, kollidon VA64 fine, dowfax2A1 and trehalose), and nanocrystalline formulation of zileuton (NfZ; at 30 mg/kg bw of the formulation). Plasma, tissue, and urine concentrations were quantified using high performance liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis showed higher zileuton levels in the plasma of female versus male rats across all evaluated forms of zileuton (API, PM, and NfZ). Female rats demonstrated higher peak plasma concentrations (Cmax) and increased area under the plasma concentration-time curve (AUC) relative to males, regardless of formulation. These findings reveal substantial gender disparities in the pharmacokinetics of zileuton in the rat model. This study emphasizes the critical need to evaluate gender differences during preclinical drug development to enable gender-based precision dosing strategies for equivalent efficacy/safety outcomes in male and female patients. Additional studies are warranted to investigate underlying mechanisms of such pharmacokinetic gender divergences.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Int J Pharm X Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Int J Pharm X Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos