The blood-brain barrier transport mechanism controlling analgesic effects of opioid drugs in CNS

Abstract

The transport of opioid analgesics across the blood-brain barrier (BBB) is an important determinant of their ther- apeutic eŠects. The human brain is protected by the BBB, which consists of brain capillary endothelial cells linked with tight junctions. It is well established that the polarized expression of numerous transporters and receptors at the brain capillary endothelial cells controls the blood-brain exchange of nutrients, waste products deriving from neurotransmitter substances, and drugs. Morphine is a substrate of P-glycoprotein and the P-glycoprotein-mediated eŒux transport at the BBB maintains a lower unbound concentration of morphine in the brain compared with plasma. On the other hand, oxycodone has 3 times higher unbound concentration in the brain than plasma, suggesting an active transport mechan- ism of oxycodone across the BBB into the brain. In vitro transport study using BBB model cells showed that oxycodone is e‹ciently transported by a proton-coupled organic cation antiporter. Human BBB model cells also retain the proton- coupled organic cation antiporter. Although adjuvant analgesics include many cationic drugs that interact with oxyco- done transport across the BBB at relatively high concentrations, these drugs would enhance the antinociceptive eŠects of oxycodone with little eŠect on oxycodone pharmacokinetics, including brain distribution at therapeutically or phar- macologically relevant concentrations. These ˆndings support the idea that proton-coupled organic cation antiporter- mediated transport of oxycodone at the BBB plays a role in determining the therapeutic e‹cacy of this opioid analgesic drug.