Pregnancy Has No Clinically Significant Effect on the Pharmacokinetics of Bupropion or Its Metabolites.
Pregnancy Has No Clinically Significant Effect on the Pharmacokinetics of Bupropion or Its Metabolites.
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DOI：
10.1097/ftd.0000000000000885
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发表时间：
2021-12-01
影响因子：
2.5
通讯作者：
Isoherranen N
中科院分区：
文献类型：
--
作者：
Fay EE;Czuba LC;Sager JE;Shum S;Stephenson-Famy A;Isoherranen N
安非他酮（BUP）是一种手性抗抑郁药和戒烟助手，其益处和副作用与母体和活性代谢物浓度相关。BUP被CYP2B6、CYP2C19和CYP3A4代谢为羟基BUP (OH-BUP)， 11β-羟基类固醇脱氢酶-1和醛酮还原酶分别代谢为三氢安非他酮（Threo）和红氢安非他酮（Erythro）。由于妊娠改变了药物代谢酶的活性，作者假设妊娠期间BUP代谢和BUP代谢物浓度会发生改变，可能影响孕妇使用BUP的疗效和安全性。纳入长期服用BUP的孕妇（n=8），在妊娠和产后收集稳态血浆样本和给药间隔尿液样本。在分娩时采集3名受试者的母体和脐带静脉血，计算脐带血/母体血浆浓度比。测定了BUP立体异构体及其代谢产物的浓度。采用配对t检验比较妊娠期和产后药代动力学参数。与产后相比，怀孕期间的稳态血浆浓度、代谢物与母体的比值、形成清除率或任何化合物的肾脏清除率均未观察到显著变化。脐带静脉血浆BUP及其代谢物浓度比母体血浆浓度低30-60%。本研究显示妊娠期间BUP及其代谢物的立体选择性配置无临床意义差异，提示妊娠期间可能不需要调整剂量。胎盘为安非他酮及其代谢物向胎儿分布提供了部分屏障，可能存在安非他酮及其代谢物的胎盘外排转运。
Bupropion (BUP) is a chiral antidepressant and smoking cessation aide with benefits and side effects correlated with parent and active metabolite concentrations. BUP is metabolized by CYP2B6, CYP2C19, and CYP3A4 to hydroxy-BUP (OH-BUP), and by 11β-hydroxysteroid dehydrogenase-1 and aldo-keto reductases to threohydrobupropion (Threo) and erythrohydrobupropion (Erythro), respectively. As pregnancy alters the activity of drug-metabolizing enzymes, the authors hypothesized that BUP metabolism and BUP metabolite concentrations, would be altered during pregnancy, potentially affecting the efficacy and safety of BUP in pregnant women. Pregnant women (n=8) taking BUP chronically were enrolled, and steady-state plasma samples and dosing interval urine samples were collected during pregnancy and postpartum. Maternal and umbilical cord venous blood samples were collected at delivery from three subjects, and cord blood/maternal plasma concentration ratios were calculated. The concentrations of BUP stereoisomers and their metabolites were measured. Paired t-tests were used to compare pharmacokinetic parameters during pregnancy and postpartum. No significant changes were observed in the steady-state plasma concentrations, metabolite to parent ratios, formation clearances, or renal clearance of any of the compounds during pregnancy when compared to postpartum. The umbilical cord venous plasma concentrations of BUP and its metabolites were 30–60% lower than maternal plasma concentrations. This study showed that there are no clinically meaningful differences in the stereoselective disposition of BUP or its metabolites during pregnancy, indicating that dose adjustment during pregnancy may not be necessary. The results also showed that the placenta provides a partial barrier for bupropion and its metabolite distribution to the fetus, with possible placental efflux transport of bupropion and its metabolites.