Cyclosporine-inhibitable cerebral drug transport does not influence clinical methadone pharmacodynamics.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Meissner, K; Blood, J; Francis, AM; Yermolenka, V; Kharasch, ED

Published Date

  • December 2014

Published In

Volume / Issue

  • 121 / 6

Start / End Page

  • 1281 - 1291

PubMed ID

  • 25072223

Pubmed Central ID

  • PMC4562501

Electronic International Standard Serial Number (EISSN)

  • 1528-1175

Digital Object Identifier (DOI)

  • 10.1097/ALN.0000000000000391


  • eng

Conference Location

  • United States