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. 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 hr). 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.

Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease

“…Similarly, methadone clearance, volume of distribution, and metabolism ( N ‐demethylation) were also comparable in the adults with SCD and healthy adult volunteers receiving IV methadone . R ‐Methadone half‐life in healthy volunteers was 48 ± 19 hr, which is comparable to our results in adults with SCD (52 ± 17 hr). Similarly, S ‐methadone half‐life was 34 ± 14 hr in healthy volunteers, and 38 ± 11 hr in our adults with SCD.…”

“…R ‐Methadone half‐life in healthy volunteers was 48 ± 19 hr, which is comparable to our results in adults with SCD (52 ± 17 hr). Similarly, S ‐methadone half‐life was 34 ± 14 hr in healthy volunteers, and 38 ± 11 hr in our adults with SCD. These results suggest that SCD in adults also does not significantly alter the pharmacokinetics of methadone.…”

Current Concepts in Methadone Metabolism and Transport

“…Nevertheless, despite this effect, there was no influence on methadone bioavailability, showing that the HIV antiretrovirals did not alter methadone intestinal absorption, and, mechanistically, that intestinal P‐gp does not mediate methadone intestinal absorption. Similarly, the multitransporter inhibitor cyclosporine delayed, but only slightly (10%), decreased oral methadone maximum plasma concentrations …”

“…An initially suspected transporter target was P‐gp because methadone was identified as a weak P‐gp substrate in vitro and in animals in vivo, where it also influenced methadone analgesia . However in clinical studies, neither quinidine nor cyclosporine, used as inhibitory in vivo probes for blood‐brain barrier P‐glycoprotein, had an influence on methadone miosis or on R‐methadone plasma concentration‐miosis relationships . That cyclosporine did, however, markedly increase human brain uptake of the known P‐gp substrate loperamide and that cyclosporine also increased apparent brain uptake of morphine suggest that P‐gp is not the principal determinant of methadone brain access in humans .…”

“…Similarly, the multitransporter inhibitor cyclosporine delayed, but only slightly (10%), decreased oral methadone maximum plasma concentrations. 45 Variability in methadone pharmacodynamics (plasma concentration-effect relationships) has been observed but is poorly understood. 8 In the abovedescribed methadone-HIV antiretroviral interaction studies, antituberculosis (rifampin) and antiretroviral (ritonavir and efavirenz) drugs did influence methadone plasma concentration-effect relationships (determined from opioid decreases in pupil diameter), suggesting a pharmacodynamic interaction occurring at the blood-brain barrier ( Figure 6B).…”