Department of Pharmacy Practice, Purdue University, Indianapolis, IN, 46202, USA.
AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA.
Eur J Drug Metab Pharmacokinet. 2023 Mar;48(2):171-187. doi: 10.1007/s13318-023-00817-9. Epub 2023 Feb 23.
Bupropion is an atypical antidepressant and smoking cessation aid; its use is associated with wide intersubject variability in efficacy and safety. Knowledge of the brain pharmacokinetics of bupropion and its pharmacologically active metabolites is considered important for understanding the cause-effect relationships driving this variability.
Brain concentrations from rats administered a 10 mg/kg subcutaneous dose of racemic bupropion were analyzed using a stereoselective LC/MS-MS method. A 2 mg/kg dose of (S,S)-hydroxybupropion, which has comparable pharmacologic potency to bupropion, was administered to a separate group of rats. Plasma exposure and unbound concentrations in both matrices from companion equilibrium dialysis experiments were determined to assess potential carrier-mediated transport at the blood-brain barrier.
Exposures to unbound forms of bupropion enantiomers were similar in plasma; this was also true in brain. This trend held for reductive diastereomer metabolite pairs in the two matrices. Unbound (R,R)-hydroxybupropion exposure was 1.5-fold higher than (S,S)-hydroxybupropion exposure in plasma and brain following bupropion administration. Unbound concentration ratios (K) of a given molecular form decreased over time: between 4 and 6 h, these were < 1 for the two bupropion enantiomers, and they were ~ 1 for metabolites that formed. Administration of preformed (S,S)-hydroxybupropion also demonstrated a declining K.
The temporal shift in K among the different molecular forms provides evidence regarding the operation of carrier-mediated transport and/or within-brain metabolism of bupropion, and, thereby, fresh insight regarding the causes of intersubject variability in the safety and efficacy of bupropion therapy.
安非他酮是一种非典型的抗抑郁药和戒烟辅助药物；其疗效和安全性存在广泛的个体间变异性。了解安非他酮及其具有药理活性的代谢物的脑药代动力学对于理解导致这种变异性的因果关系非常重要。
使用立体选择性 LC/MS-MS 方法分析了给予大鼠 10mg/kg 皮下剂量外消旋安非他酮后的脑浓度。给予另一组大鼠 2mg/kg 剂量的（S，S）-羟基安非他酮，其药理效力与安非他酮相当。从配套的平衡透析实验中测定两种基质中的血浆暴露量和未结合浓度，以评估血脑屏障中潜在的载体介导转运。
在血浆中，安非他酮对映体的未结合形式的暴露相似；在脑中也是如此。这种趋势在两种基质中的还原非对映异构体代谢物对中保持不变。在给予安非他酮后，未结合的（R，R）-羟基安非他酮暴露在血浆和脑中是（S，S）-羟基安非他酮的 1.5 倍。未结合浓度比（K）随时间推移而降低：在 4 至 6 小时之间，两种安非他酮对映体的 K<1，形成的代谢物的 K 约为 1。预先形成的（S，S）-羟基安非他酮的给药也显示出 K 的下降。
不同分子形式之间 K 的时间推移提供了关于载体介导转运和/或安非他酮在脑内代谢的证据，从而为安非他酮治疗的安全性和疗效的个体间变异性的原因提供了新的见解。
