* Associate Professor of Anesthesiology, Universitätsmedizin Greifswald, Klinik für Anästhesiologie und Intensivmedizin, Greifswald, Germany, and Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St. Louis, St. Louis, Missouri. † Associate Professor of Anesthesiology, Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. ‡ Research Technician, § Clinical Research Coordinator, ‖ Head Research Nurse, Department of Anesthesiology, Washington University in St. Louis. # Russell D. and Mary B. Shelden Professor of Anesthesiology, Professor of Biochemistry and Molecular Biophysics, Vice-Chancellor for Research, Departments of Anesthesiology and Biochemistry and Molecular Biophysics, Division of Clinical and Translational Research, Washington University in St. Louis.
Anesthesiology. 2013 Oct;119(4):941-53. doi: 10.1097/ALN.0b013e3182a05bd3.
The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans.
Fourteen healthy volunteers received morphine (0.1 mg/kg, 1-h IV infusion) in a crossover study without (control) or with the infusion of validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2-h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia.
Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml·h (P < 0.05) without changing maximum plasma concentration. Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm·h), plasma effect-site transfer rate constant (k(e0), median 0.27 vs. 0.17 h(-1)), and maximum calculated effect-site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml; all P < 0.05). Analgesia testing was confounded by cyclosporine-related pain.
Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects.
血脑屏障富含主动摄取和外排转运体，影响脑内药物浓度。吗啡是一种起效时间延迟的药物，在体外和动物模型中是外排转运体 P 糖蛋白的底物。本研究旨在检测吗啡是否也是人体的转运体底物。
14 名健康志愿者交叉接受吗啡（0.1mg/kg，1 小时静脉输注），并分别在无（对照）或有环孢素（5mg/kg，2 小时输注）的情况下输注，验证其对 P 糖蛋白的抑制作用。采用质谱法测定血浆和尿液中的吗啡及其葡萄糖醛酸代谢物浓度。通过瞳孔缩小和镇痛作用来评估吗啡的效应。
环孢素对吗啡的处置影响较小，使血浆吗啡浓度-时间曲线下面积增加至 100±21ng/ml·h 对 85±24ng/ml·h（P＜0.05），但最大血浆浓度无变化。环孢素增强（3.2±0.9 对 2.5±1.0mm 峰值）并延长了瞳孔缩小，增加了瞳孔缩小时间曲线下面积（18±9 对 11±5mm·h），血浆效应部位转运速率常数（k(e0)，中位数 0.27 对 0.17h(-1))和最大计算效应部位吗啡浓度（11.5±3.7 对 7.6±2.9ng/ml；均 P＜0.05）。环孢素相关疼痛使镇痛测试结果受到干扰。
吗啡是人体血脑屏障的转运体底物。结果提示 P 糖蛋白或其他外排转运体可能在脑内吗啡摄取中发挥作用，尽管其作用幅度较小，不太可能是吗啡临床效应的主要决定因素。外排可能解释了吗啡临床效应的一些变异性。
