• Konrad Meissner, Michael J Avram, Viktar Yermolenka, Amber M Francis, Jane Blood, and Evan D Kharasch.
• * 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 1;119(4):941-53.

BackgroundThe 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.MethodsFourteen 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.ResultsCyclosporine 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.ConclusionsMorphine 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.

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