1. Population Pharmacokinetics of Sulindac and Genetic Polymorphisms of FMO3 and AOX1 in Women with Preterm Labor
- Author
-
Byungjeong Song, Jeong Yee, Hye Sun Gwak, Sunny Park, Hwi-yeol Yun, Kyung Eun Lee, Jee Eun Chung, Young Ju Kim, and Jin Won Sung
- Subjects
Adult ,Genotype ,Population ,Anti-Inflammatory Agents ,Pharmaceutical Science ,Gestational Age ,02 engineering and technology ,Pharmacology ,Models, Biological ,030226 pharmacology & pharmacy ,03 medical and health sciences ,Obstetric Labor, Premature ,Sulindac ,0302 clinical medicine ,Pharmacokinetics ,Pregnancy ,Oral administration ,medicine ,Humans ,Pharmacology (medical) ,Prospective Studies ,education ,Active metabolite ,Volume of distribution ,education.field_of_study ,Polymorphism, Genetic ,business.industry ,Organic Chemistry ,Gestational age ,021001 nanoscience & nanotechnology ,digestive system diseases ,NONMEM ,Aldehyde Oxidase ,Oxygenases ,Molecular Medicine ,Female ,0210 nano-technology ,business ,Signal Transduction ,Biotechnology ,medicine.drug - Abstract
This prospective study aimed to evaluate the effects of genetic polymorphisms in sulindac-related metabolizing enzyme genes including FMO3 and AOX1 on the population pharmacokinetics of sulindac in 58 pregnant women with preterm labor. Plasma samples were collected at 1.5, 4, and 10 h after first oral administration of sulindac. Plasma concentrations of sulindac and its active metabolite (sulindac sulfide) were determined, and pharmacokinetic analysis was performed with NONMEM 7.3. The mean maternal and gestational ages at the time of dosing were 32.5 ± 4.4 (range, 20โ41) years and 27.4 ± 4.4 (range, 16.4โ33.4) weeks, respectively. In the population pharmacokinetic analysis, one depot compartment model of sulindac with absorption lag time best described the data. The metabolism of sulindac and sulindac sulfide was described using Michaelis-Menten kinetics. In stepwise modeling, gestational age impacted volume of distribution (Vc), and FMO3 rs2266782 was shown by the Michaelis constant to affect conversion of sulindac sulfide to sulindac (KM32); these were retained in the final model. Genetic polymorphisms of FMO3 and AOX1 could affect the pharmacokinetics of sulindac in women who undergo preterm labor. The results of this study could help clinicians develop individualized treatment plans for administering sulindac.
- Published
- 2020
- Full Text
- View/download PDF