Wang Jun-Sheng, DeVane C Lindsay, Gibson B Bryan, Donovan Jennifer L, Markowitz John S, Zhu Hao-Jie
Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, Charleston, SC 29425, USA.
Psychopharmacology (Berl). 2006 Jan;183(4):490-9. doi: 10.1007/s00213-005-0209-y. Epub 2005 Nov 9.
Accumulating evidence indicates that modulation of the activity of cytochrome P450 (CYP) enzymes and the multidrug resistance transporter P-glycoprotein (P-gp) is responsible for many drug-drug interactions.
The potential interaction of risperidone (RISP), which is metabolized by 2D6 and transported across the blood brain barrier (BBB) by P-gp, was studied in combination with bupropion (BUP) and also with sertraline (SERT).
BUP, SERT, and RISP were administered intraperitoneally into CF1 mice at doses of 100, 10, and 1 microg/g mouse, respectively. Plasma and brain samples were collected at timed intervals from 0.5 to 6 h. A pharmacokinetic analysis was performed using both traditional compartmental modeling and a population pharmacokinetic approach.
BUP increased the RISP plasma (5.9-fold, P<0.01) and brain (2.2-fold, P<0.01) area under the drug concentration vs time curve (AUC), but did not alter the brain-to-plasma concentration ratio. SERT did not significantly change the plasma AUC of RISP and 9-hydroxy-RISP, but increased the brain AUC of RISP and 9-hydroxy-RISP 1.5-fold (P<0.05) and 5-fold (P<0.01), respectively. RISP did not produce significant alterations of plasma or brain concentrations of BUP. It increased the plasma AUC and elimination half-life (T1/2e) of desmethyl-SERT 12.5-fold (P<0.01) and 107-fold (P<0.01), respectively.
These results suggest that pharmacokinetic interactions exist among these three psychoactive drugs involving inhibition of drug metabolizing enzymes and/or P-gp and other drug transporters present in the BBB. The mechanisms and consequences of these interactions require further study in humans to establish clinical relevance.
越来越多的证据表明，细胞色素P450（CYP）酶和多药耐药转运蛋白P-糖蛋白（P-gp）活性的调节是许多药物相互作用的原因。
研究利培酮（RISP）与安非他酮（BUP）以及与舍曲林（SERT）联合使用时的潜在相互作用。RISP由2D6代谢，并通过P-gp转运穿过血脑屏障（BBB）。
分别以100、10和1μg/g小鼠的剂量将BUP、SERT和RISP腹腔注射到CF1小鼠体内。在0.5至6小时的时间间隔内收集血浆和脑样本。使用传统的房室模型和群体药代动力学方法进行药代动力学分析。
BUP增加了RISP的血浆药物浓度-时间曲线下面积（AUC）（5.9倍，P<0.01）和脑AUC（2.2倍，P<0.01），但未改变脑-血浆浓度比。SERT没有显著改变RISP和9-羟基-RISP的血浆AUC，但分别使RISP和9-羟基-RISP的脑AUC增加了1.5倍（P<0.05）和5倍（P<0.01）。RISP没有显著改变BUP的血浆或脑浓度。它分别使去甲基-SERT的血浆AUC和消除半衰期（T1/2e）增加了12.5倍（P<0.01）和107倍（P<0.01）。
这些结果表明，这三种精神活性药物之间存在药代动力学相互作用，涉及抑制药物代谢酶和/或BBB中存在的P-gp和其他药物转运蛋白。这些相互作用的机制和后果需要在人体中进一步研究以确定临床相关性。
