ABSTRACT:The blood-brain barrier (BBB) transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120-min constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another 10 animals were given a 60-min constant rate infusion to study the rate of equilibration across the BBB. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM. A two-compartment model which allowed for a delay between the venous and arterial compartments best described the pharmacokinetics for oxycodone in blood and plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CL in and K p,uu . CL in describes the clearance of oxycodone across the BBB into the brain, whereas K p,uu describes the extent of drug equilibration across the BBB. CL in across the BBB was estimated to 1910 l/min ⅐ g brain. K p,uu was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids.The blood-brain barrier (BBB) is composed of capillary endothelial cells connected by tight junctions. Its main function is to be a physical and active barrier to restrict and regulate the penetration of compounds into and out from the brain to maintain brain homeostasis. Transport into the brain across the BBB is essential for drugs that act within the central nervous system (CNS), whereas BBB penetration needs to be minimized for drugs with potential CNS side effects. Brain distribution can be described with respect to the rate and extent of equilibration of a drug molecule across the BBB (Hammarlund-Udenaes, 2000). The rate of equilibration can be expressed as clearances into and out of the brain, CL in and CL out , respectively. The extent of equilibration across the BBB can be expressed as the ratio of the steady-state concentration of unbound drug in brain over unbound drug in blood, K p,uu (Gupta et al., 2006). K p,uu is equivalent to the ratio of the area under the concentration versus time curve of unbound drug in brain and blood, AUC u,brain /AUC u,blood , as well as to the ratio CL in /CL out . This assumes that it is only unbound drug that crosses the BBB and that metabolism and interstitial bulk flow contribution to brain efflux is minor. The extent of equilibration equals the net flux of drug across the BBB.Conclusions on the bidirectional transport properties of the BBB can be drawn based on the unbound concentrations in brain an...

For centrally acting drugs such as opioids, pharmacokinetic-pharmacodynamic relations describing the interaction with the receptor are better obtained by correlating the effects to concentrations of unbound drug in the tissue of interest rather than to blood concentrations.

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The histamine H3 receptor represents an appealing central nervous system drug target due to its important role in the neurobiology of cognition and wake-sleep regulation. The therapeutic benefit of H3 antagonists/inverse agonists may be hampered by disruption of sleep that has been observed in humans with prolonged high H3 receptor occupancy (H3RO), extending into night-time. AZD5213 is a highly selective H3 antagonist (in vitro inverse agonist) developed to achieve a pharmacokinetic profile permitting circadian fluctuations of H3RO. Its efficacy has been demonstrated in rodent behavioural models of cognition. In human subjects, AZD5213 was safe and well tolerated following repeated doses (1-14 mg/d) and demonstrated a short (∼5 h) half-life. In this PET study H3RO was measured using the radioligand [11C]GSK189254 ([11C]AZ12807110) in seven young male volunteers following single doses of AZD5213 (0.05-30 mg). H3RO was calculated using the Lassen plot method. The plasma concentrations and the affinity constant (K i,pl 1.14 nmol/l, corresponding to the plasma concentration required to occupy 50% of available receptors) were used to estimate the H3RO time-course. AZD5213 showed dose and concentration dependent H3RO ranging from 16 to 90%. These binding characteristics and the pharmacokinetic profile of AZD5213 indicate that high daytime and low night-time H3RO could be achieved following once daily oral dosing of AZD5213. Fluctuations of H3RO following circadian rhythm of the histamine system may be expected to reduce the risk of sleep disruption while maintaining daytime efficacy. AZD5213 may thus be an optimal compound to evaluate the clinical benefit of selective H3 antagonism in cognitive disorders.

Morphine is transferred via olfactory pathways to the brain hemispheres, and drug transfer via this route significantly contributes to the early high brain concentrations after nasal administration to rats.