Masters Andrea R, Gufford Brandon T, Lu Jessica Bo Li, Metzger Ingrid F, Jones David R, Desta Zeruesenay
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
J Pharmacol Exp Ther. 2016 Aug;358(2):230-8. doi: 10.1124/jpet.116.232876. Epub 2016 Jun 2.
Bupropion, widely used as an antidepressant and smoking cessation aid, undergoes complex metabolism to yield numerous metabolites with unique disposition, effect, and drug-drug interactions (DDIs) in humans. The stereoselective plasma and urinary pharmacokinetics of bupropion and its metabolites were evaluated to understand their potential contributions to bupropion effects. Healthy human volunteers (n = 15) were administered a single oral dose of racemic bupropion (100 mg), which was followed by collection of plasma and urine samples and determination of bupropion and metabolite concentrations using novel liquid chromatography-tandem mass spectrometry assays. Time-dependent, elimination rate-limited, stereoselective pharmacokinetics were observed for all bupropion metabolites. Area under the plasma concentration-time curve from zero to infinity ratios were on average approximately 65, 6, 6, and 4 and Cmax ratios were approximately 35, 6, 3, and 0.5 for (2R,3R)-/(2S,3S)-hydroxybupropion, R-/S-bupropion, (1S,2R)-/(1R,2S)-erythrohydrobupropion, and (1R,2R)-/(1S,2S)-threohydrobupropion, respectively. The R-/S-bupropion and (1R,2R)-/(1S,2S)-threohydrobupropion ratios are likely indicative of higher presystemic metabolism of S- versus R-bupropion by carbonyl reductases. Interestingly, the apparent renal clearance of (2S,3S)-hydroxybupropion was almost 10-fold higher than that of (2R,3R)-hydroxybupropion. The prediction of steady-state pharmacokinetics demonstrated differential stereospecific accumulation [partial area under the plasma concentration-time curve after the final simulated bupropion dose (300-312 hours) from 185 to 37,447 nM⋅h] and elimination [terminal half-life of approximately 7-46 hours] of bupropion metabolites, which may explain observed stereoselective differences in bupropion effect and DDI risk with CYP2D6 at steady state. Further elucidation of bupropion and metabolite disposition suggests that bupropion is not a reliable in vivo marker of CYP2B6 activity. In summary, to our knowledge, this is the first comprehensive report to provide novel insight into mechanisms underlying bupropion disposition by detailing the stereoselective pharmacokinetics of individual bupropion metabolites, which will enhance clinical understanding of bupropion's effects and DDIs with CYP2D6.
安非他酮被广泛用作抗抑郁药和戒烟辅助药物，其代谢过程复杂，会产生多种具有独特处置方式、效应及药物相互作用（DDIs）的代谢产物。对安非他酮及其代谢产物的立体选择性血浆和尿液药代动力学进行了评估，以了解它们对安非他酮效应的潜在影响。健康人类志愿者（n = 15）口服单剂量消旋安非他酮（100 mg），随后采集血浆和尿液样本，并使用新型液相色谱 - 串联质谱分析法测定安非他酮及其代谢产物的浓度。观察到所有安非他酮代谢产物均呈现出时间依赖性、消除速率受限的立体选择性药代动力学特征。对于（2R,3R）- /（2S,3S）-羟基安非他酮、R- / S-安非他酮、（1S,2R）- /（1R,2S）-赤藓醇羟基安非他酮和（1R,2R）- /（1S,2S）-苏阿糖醇羟基安非他酮，从零到无穷大的血浆浓度 - 时间曲线下面积比值平均分别约为65、6、6和4，Cmax比值分别约为35、6、3和0.5。R- / S-安非他酮和（1R,2R）- /（1S,2S）-苏阿糖醇羟基安非他酮的比值可能表明羰基还原酶对S-安非他酮的首过代谢高于R-安非他酮。有趣的是，（2S,3S）-羟基安非他酮的表观肾清除率几乎比（2R,3R）-羟基安非他酮高10倍。稳态药代动力学预测表明，安非他酮代谢产物存在差异立体特异性蓄积[末次模拟安非他酮剂量（300 - 312小时）后血浆浓度 - 时间曲线下部分面积为185至37447 nM·h]和消除[终末半衰期约为7 - 46小时]，这可能解释了在稳态下观察到的安非他酮效应和与CYP2D6的药物相互作用风险中的立体选择性差异。对安非他酮及其代谢产物处置的进一步阐明表明，安非他酮并非CYP2B6活性可靠的体内标志物。总之，据我们所知，这是第一份全面报告，通过详细阐述单个安非他酮代谢产物的立体选择性药代动力学，为安非他酮处置的潜在机制提供了新的见解，这将增强对安非他酮效应以及与CYP2D6药物相互作用的临床理解。
