妊娠对布比卡因及其代谢物的药代动力学无临床显著影响。
Pregnancy Has No Clinically Significant Effect on the Pharmacokinetics of Bupropion or Its Metabolites.
机构信息
Department of Obstetrics and Gynecology, University of Washington School of Medicine; and.
Department of Pharmaceutics, University of Washington School of Pharmacy, Seattle, Washington.
出版信息
Ther Drug Monit. 2021 Dec 1;43(6):780-788. doi: 10.1097/FTD.0000000000000885.
BACKGROUND
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) as well as 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.
METHODS
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 3 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.
RESULTS
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 with postpartum. The umbilical cord venous plasma concentrations of BUP and its metabolites were 30%-60% lower than maternal plasma concentrations.
CONCLUSIONS
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.
背景
安非他酮（BUP）是一种手性抗抑郁药和戒烟辅助药物，其疗效和副作用与母体和活性代谢物浓度相关。BUP 通过 CYP2B6、CYP2C19 和 CYP3A4 代谢为羟基安非他酮（OH-BUP），以及通过 11β-羟甾体脱氢酶-1 和醛酮还原酶分别代谢为 threohydrobupropion（Threo）和 erythrohydrobupropion（Erythro）。由于妊娠改变了药物代谢酶的活性，作者假设 BUP 代谢和 BUP 代谢物浓度会在妊娠期间发生变化，这可能会影响 BUP 在孕妇中的疗效和安全性。
方法
招募了 8 名慢性服用 BUP 的孕妇，并在妊娠和产后期间采集了稳态血浆样本和给药间隔尿液样本。在 3 名受试者分娩时采集了母体和脐静脉血样本，并计算了脐血/母体血浆浓度比。测量了 BUP 立体异构体及其代谢物的浓度。采用配对 t 检验比较了妊娠和产后期间的药代动力学参数。
结果
与产后相比，妊娠期间母体和胎儿血浆中 BUP 及其代谢物的稳态血浆浓度、母体/代谢物比值、形成清除率或肾清除率均无显著变化。BUP 及其代谢物的脐静脉血浆浓度比母体血浆浓度低 30%-60%。
结论
本研究表明，妊娠期间 BUP 及其代谢物的立体选择性分布没有临床意义上的差异，这表明妊娠期间不需要调整剂量。结果还表明，胎盘对 BUP 及其代谢物向胎儿的分布提供了部分屏障，可能存在 BUP 及其代谢物的胎盘外排转运。
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