Kharasch Evan D, Mitchell Darain, Coles Rebecka
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St. Louis, MO 63110-1093, USA.
J Clin Pharmacol. 2008 Apr;48(4):464-74. doi: 10.1177/0091270008314254. Epub 2008 Feb 20.
The clearance of racemic bupropion, metabolized selectively by CYP2B6 in vitro, has been used clinically to phenotype CYP2B6 activity, polymorphisms, and drug interactions but has known limitations. Bupropion hydroxylation by CYP2B6 is stereoselective. This investigation assessed the stereoselectivity of bupropion pharmacokinetics and the influence of CYP2B6 induction. Ten healthy volunteers received immediate-release bupropion before and after 7 days of rifampin. Plasma and urine bupropion and hydroxybupropion were analyzed using a stereoselective assay. Plasma area under the curve (AUC(0-infinity)) and maximum concentrations were 3-fold greater for R- than S-bupropion. Bupropion apparent oral clearance was 3- and 2-fold greater for S- than R- and R,S-bupropion, respectively. Hydroxybupropion plasma AUC(0-infinity) and elimination half-life were significantly less for (S,S)- than (R,R)- and the racemate. (S,S)-hydroxybupropion was formation rate limited, whereas (R,R)-hydroxybupropion and the racemate were elimination rate limited. Rifampin doubled both R- and S-bupropion clearance and caused 4-fold increases in both (R,R)- and (S,S)-hydroxybupropion formation clearances. Increases in the plasma hydroxybupropion/bupropion AUC(0-infinity) ratio were greater for (S,S)- than (R,R)-hydroxybupropion. Simplified plasma and urine metrics of stereoselective bupropion metabolism and clearance were identified. Because metabolite formation clearance is the best in vivo metric of enzyme activity and due, therefore, to faster S-bupropion elimination and formation rate-limited (S,S)-hydroxybupropion kinetics, stereoselective S-bupropion hydroxylation and (S,S)-hydroxybupropion formation clearance may be a useful and improved phenotypic probe for CYP2B6.
消旋安非他酮在体外经CYP2B6选择性代谢，其清除率已在临床上用于表型分析CYP2B6活性、多态性及药物相互作用，但存在已知局限性。CYP2B6对安非他酮的羟基化具有立体选择性。本研究评估了安非他酮药代动力学的立体选择性及CYP2B6诱导的影响。10名健康志愿者在服用利福平7天前后分别服用速释型安非他酮。采用立体选择性分析法分析血浆和尿液中的安非他酮及羟基安非他酮。R-安非他酮的血浆曲线下面积（AUC(0-∞)）和最大浓度比S-安非他酮高3倍。S-安非他酮的表观口服清除率分别比R-安非他酮和消旋安非他酮高3倍和2倍。(S,S)-羟基安非他酮的血浆AUC(0-∞)和消除半衰期显著短于(R,R)-羟基安非他酮和消旋体。(S,S)-羟基安非他酮的形成速率受限，而(R,R)-羟基安非他酮和消旋体的消除速率受限。利福平使R-和S-安非他酮的清除率均增加一倍，并使(R,R)-和(S,S)-羟基安非他酮的形成清除率均增加4倍。(S,S)-羟基安非他酮的血浆羟基安非他酮/安非他酮AUC(0-∞)比值增幅大于(R,R)-羟基安非他酮。确定了安非他酮立体选择性代谢和清除的简化血浆和尿液指标。由于代谢物形成清除率是体内酶活性的最佳指标，因此，由于S-安非他酮消除更快且(S,S)-羟基安非他酮动力学受形成速率限制，立体选择性S-安非他酮羟基化和(S,S)-羟基安非他酮形成清除率可能是一种有用且改进的CYP2B6表型探针。
