College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Ewhayeodae-gil Seodaemun-Gu, Seoul, 03760, Republic of Korea.
College of Pharmacy, Chungnam National University, Daejeon, 34134, South Korea.
Pharm Res. 2020 Jan 28;37(3):44. doi: 10.1007/s11095-020-2765-6.
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, 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 (K); 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.
本前瞻性研究旨在评估与舒林酸相关代谢酶基因（包括 FMO3 和 AOX1）的遗传多态性对 58 例早产孕妇舒林酸群体药代动力学的影响。
在首次口服舒林酸后 1.5、4 和 10 小时采集血浆样本。测定舒林酸及其活性代谢物（舒林酸亚砜）的血浆浓度，并采用 NONMEM 7.3 进行药代动力学分析。
给药时母亲和妊娠年龄的平均值分别为 32.5±4.4（范围，20-41）岁和 27.4±4.4（范围，16.4-33.4）周。在群体药代动力学分析中，舒林酸的一个储库模型结合吸收滞后时间能最好地描述数据。舒林酸和舒林酸亚砜的代谢采用米氏动力学描述。在逐步建模中，妊娠年龄影响分布容积（Vc），FMO3 rs2266782 则通过米氏常数显示出影响舒林酸亚砜向舒林酸的转化（K）；这些因素被保留在最终模型中。
FMO3 和 AOX1 的遗传多态性可能会影响早产孕妇舒林酸的药代动力学。本研究结果有助于临床医生制定个体化的舒林酸治疗方案。
