Drug-drug interaction between oxycodone and adjuvant analgesics in blood-brain barrier transport and antinociceptive effect

Yusuke Nakazawa, Takashi Okura, Keita Shimomura, Tetsuya Terasaki, Yoshiharu Deguchi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

To examine possible blood-brain barrier (BBB) transport interactions between oxycodone and adjuvant analgesics, we firstly screened various candidates in vitro using [3H]pyrilamine, a substrate of the oxycodone transporter, as a probe drug. The uptake of [3H]pyrilamine by conditionally immortalized rat brain capillary endothelial cells (TR-BBB13) was inhibited by antidepressants (amitriptyline, imipramine, clomipramine, amoxapine, and fluvoxamine), antiarrhythmics (mexiletine, lidocaine, and flecainide), and ketamine. On the other hand, antiepileptics (carbamazepine, phenytoin, and clonazepam) and corticosteroids (dexamethasone and prednisolone) did not inhibit [3H]pyrilamine uptake, with the exception of sodium valproate. The uptake of oxycodone was significantly inhibited in a concentrationdependent manner by amitriptyline, fluvoxamine and mexiletine with Ki values of 13, 65, and 44 μM, respectively. These Ki values are 5-300 times greater than the human therapeutic plasma concentrations. Finally, we evaluated in vivo interaction between oxycodone and amitriptyline in mice. Antinociceptive effects of oxycodone were increased by coadministration of amitriptyline. The oxycodone concentrations in plasma and brain were not changed by coadministration of amitriptyline. Overall, the results suggest that several adjuvant analgesics may interact with the BBB transport of oxycodone at relatively high concentrations. However, it is unlikely that there would be any significant interaction at therapeutically or pharmacologically relevant concentrations.

Original languageEnglish
Pages (from-to)467-474
Number of pages8
JournalJournal of Pharmaceutical Sciences
Volume99
Issue number1
DOIs
Publication statusPublished - 2010 Jan

Keywords

  • Adjuvant analgesic
  • Blood-brain barrier
  • CNS
  • Distribution
  • Drug interactions
  • Oxycodone
  • Pyrilamine
  • Transporters

ASJC Scopus subject areas

  • Pharmaceutical Science

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