Jin Won Sung1, Hwi-Yeol Yun2, Sunny Park1, Young Ju Kim3, Jeong Yee1, Kyung Eun Lee4, Byungjeong Song2, Jee Eun Chung5, Hye Sun Gwak6. 1. College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Ewhayeodae-gil Seodaemun-Gu, Seoul, 03760, Republic of Korea. 2. College of Pharmacy, Chungnam National University, Daejeon, 34134, South Korea. 3. Department of Obstetrics and Gynecology, Ewha Womans University School of Medicine, Seoul, 07985, South Korea. 4. College of Pharmacy, Chungbuk National University, Cheongju, 28644, South Korea. 5. College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdeahak-ro, Sangnok-gu, Ansan, Gyeonggido, 15588, South Korea. jechung@hanyang.ac.kr. 6. College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Ewhayeodae-gil Seodaemun-Gu, Seoul, 03760, Republic of Korea. hsgwak@ewha.ac.kr.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: The mean maternal and gestational ages at the time of dosing were 32.5 ± 4.4 (range, 20-41) years and 27.4 ± 4.4 (range, 16.4-33.4) 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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. RESULTS: The mean maternal and gestational ages at the time of dosing were 32.5 ± 4.4 (range, 20-41) years and 27.4 ± 4.4 (range, 16.4-33.4) 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 FMO3rs2266782 was shown by the Michaelis constant to affect conversion of sulindac sulfide to sulindac (KM32); these were retained in the final model. CONCLUSIONS: 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.
Entities:
Keywords:
AOX1; FMO3; Sulindac; population pharmacokinetics; preterm labor
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