Pharmacokinetic aspects of the blood-brain barrier transport and equilibration of opioids studied with microdialysis in rats and mice

Sammanfattning: The blood-brain barrier (BBB) transport and equilibration of opioids with different physico-chemical properties and similar structures - codeine, morphine, morphine3-glucuronide (M3G) and morphine-6-glucuronide (M6G) - were investigated in rats and mice using microdialysis. The influences of active efflux pumps, P-glycoprotein (Pgp) and multidrug resistance protein (MRP1), on the BBB transport of morphine and M3G were studied. Modeling of the BBB transport was performed in NONMEM to estimate the intlux and efflux clearances (CLin and CLout). Simulations were performed on the different possible transport processes at the BBB: passive diffusion, influx hindrance, active efflux, or a combination of influx hindrance and active efflux.Codeine was rapidly transported into the brain and quickly reached BBB equilibration with an unbound area under the concentration-time curve (AUC) ratio of brain extracellular fluid (ECF) to blood of 1.0 ± 0.2. The unbound morphine concentration ratio of brain ECF to blood at the end of infusion was 0.5 ± 0.4 in mdrla (+/+) mice and 0.9 ± 0.4 in mdrla (-/-) mice lacking Pgp. The brain ECF-to-blood unbound steady-state concentration ratio of M6G was 0.22± 0.09, while it was 0.10 ± 0.04 for M3G. The ratio for M3G was increased to 0.16 ± 0.05 during co-administration of probenecid, an inhibitor of MRP1. From the modeling analysis, it was shown that CLout of M3G and M6G (1.15 and 2.17 μl/min'g-brain, respectively) were significantly higher than the CLin (0.11 and 0.35 μl/min'g-brain, respectively). These results indicate that the BBB transport of codeine is dominated by passive diffusion, that Pgp contributes to lower the brain concentration of morphine, that MRP1 is involved in the BBB transport of M3G. and that one or both active efflux pumps are active on M6G.All studied opioids had similar half-lives in blood (20-24 min). Longer half-lives were found in brain ECF for M6G (58 ± 17 min) and M3G (81 ± 25 min). Codeine's half-life was similar to that in blood (brain 24 ± 5 min VS. blood 26 ± 3 min. Together with the need for two compartments in the modeling to describe the concentration-time profiles in the brain for M3G and M6G, this indicates that the redistribution within the brain is the rate-limiting step for the elimination of M3G and M6G from the. brain, not the BBB transport itself.Simulations showed that influx hindrance is mom efficient in restraining the drug transport into the brain than active efflux, and it does not affect the half-life in brain. The most powerful mechanism to lower brain concentration is a combination of influx hindrance and active efflux processes, which is the most physiologically plausible process.