title: Cyclosporine-inhibitable cerebral drug transport does not influence clinical methadone pharmacodynamics.
abstract: BACKGROUND
  Interindividual 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].
  
  
  METHODS
  Healthy 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).
  
  
  RESULTS
  Cyclosporine 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.
  
  
  CONCLUSIONS
  Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution.
authors: 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.
authors: Konrad
authors: K
authors: Meissner
authors: Jane
authors: J
authors: Blood
authors: Amber M
authors: AM
authors: Francis
authors: Viktar
authors: V
authors: Yermolenka
authors: Evan D
authors: ED
authors: Kharasch
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D008691:Methadone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D015877:Miosis; D010147:Pain Measurement / Q000187:drug effects; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D008691:Methadone