• Konrad Meissner, Jane Blood, Amber M Francis, Viktar Yermolenka, and Evan D Kharasch.
• From the Department of Anesthesiology, Universitätsmedizin Greifswald, Greifswald, Germany (K.M.); and Departments of Anesthesiology (K.M., J.B., A.M.F., V.Y., E.D.K.) and of Biochemistry and Molecular Biophysics (E.D.K.), Washington University in St. Louis, St. Louis, Missouri.
• Anesthesiology. 2014 Dec 1; 121 (6): 1281-91.

BackgroundInterindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter substrate in humans [corrected].MethodsHealthy volunteers received oral (N=16) or IV (N=12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 h). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures).ResultsCyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4±0.4 and 1.3±0.5 mm/mg, respectively) and IV methadone (3.1±1.0 and 3.2±0.8 mm, respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain.ConclusionsCyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution.

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