Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo

Muhammad Waqas Sadiq, Annika Borgs, Takashi Okura, Keita Shimomura, Sayaka Kato, Yoshiharu Deguchi, Britt Jansson, Sven Björkman, Tetsuya Terasaki, Margareta Hammarlund-udenaes

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

Diphenhydramine (DPHM) and oxycodone are weak bases that are able to form cations. Both drugs show active uptake at the blood-brain barrier (BBB). There is thus a possibility for a pharmacokinetic interaction between them by competition for the same uptake transport system. The experiments of the present study were designed to study the transport of DPHM across the BBB and its interaction with oxycodone in vitro and in vivo. In vitro, the interaction between the drugs was studied using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13 cells). The in vivo relevance of the in vitro findings was studied in rats using brain and blood microdialysis. DPHM was actively transported across the BBB in vitro (TR-BBB13 cells). Oxycodone competitively inhibited DPHM uptake with a K i value of 106μM. DPHM also competitively inhibited oxycodone uptake with a K i value of 34.7μM. In rats, DPHM showed fivefold higher unbound concentration in brain interstitial fluid (ISF) than in blood, confirming a net active uptake. There was no significant interaction between DPHM and oxycodone in vivo. This accords with the results of the in vitro experiments because the unbound plasma concentrations that could be attained in vivo, without causing adverse effects, were far below the K i values.

Original languageEnglish
Pages (from-to)3912-3923
Number of pages12
JournalJournal of Pharmaceutical Sciences
Volume100
Issue number9
DOIs
Publication statusPublished - 2011 Jan 1

Keywords

  • Active transport
  • Blood-brain barrier
  • Drug interactions
  • HPLC (high-performance/pressure liquid chromatography)
  • Mass spectrometry
  • Organic cation transporters (OCTs)
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmaceutical Science

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